Piperdine cxcr7 receptor modulators

ABSTRACT

The present invention relates to piperidine derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein Ar 1 , Ar 2 , R Ar1 , R 1 , R 2  and R 3  are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as CXCR7 receptor modulators.

The present invention relates to novel piperidine derivatives of formula(I) which are suited as pharmaceuticals which are modulators of theCXCL11/CXCL12 receptor CXCR7, and to related aspects including processesfor the preparation of the compounds of formula (I), pharmaceuticalcompositions containing one or more compounds of formula (I), and to theuse of the compounds of formula (I) as modulators of the CXCL11/CXCL12receptor CXCR7. The invention further relates to the compounds offormula (I) and their use as pharmaceuticals in combination with one ormore therapeutic agents and/or radiotherapy and/or targeted therapy inthe treatment of cancers (especially brain tumors including malignantgliomas, glioblastoma multiforme; neuroblastoma; pancreatic cancerincluding pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma;gastro-intestinal cancers including colon carcinoma, hepatocellularcarcinoma; Kaposi's sarcoma; leukemias including adult T-cell leukemia;lymphoma; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer;esophageal squamous cancer; oral squamous cell carcinoma; endometrialcancer; thyroid carcinoma including papillary thyroid carcinoma;metastatic cancers; lung metastasis; skin cancer including melanoma andmetastatic melanoma; bladder cancer; multiple myelomas; osteosarcoma;head and neck cancer; and renal carcinomas including renal clear cellcarcinoma, metastatic renal clear cell carcinoma).

Chemokine receptors are a group of G-protein coupled receptors (GPCRs)that bind peptidic chemokine ligands with high affinity. The predominantfunction of chemokine receptors is to guide leukocyte trafficking tolymphoid organs and tissues under resting conditions as well as duringinflammation, but a role for certain chemokine receptors onnon-hematopoietic cells and their progenitors has also been recognized.

CXCR7 (alias ACKR3, alias RDC1, alias CMKOR1, alias GPR159) has twoknown chemokine ligands: CXCL12 (alias stromal cell-derived factor 1,SDF-1; alias Pre-B cell growth stimulating factor, PBSF) and CXCL11(alias I-TAC, alias INF-y-inducible T cell a chemo-attractant).

CXCL12, a stroma-derived chemo-attractant participates in the immunesurveillance and in the regulation of inflammatory responses. CXCL12 issecreted by bone marrow stromal cells, endothelial cells, heart,skeletal muscle, liver, brain, kidney, parenchymal cells and play anessential role in stem cell proliferation, survival, and homing ofhematopoietic/progenitor to the bone marrow (Rankin S M et al.;Chemokine and adult bone marrow stem cells; Immunol let. 2012,145(1-2):47-54). CXCL12 also recruits bone-marrow derived progenitorcells to sites of vasculature formation. Moreover, it plays a prominentrole in carcinogenesis. CXCL12 promotes the recruitment of endothelialprogenitor cells and of myeloid derived suppressor cells to the tumorsites as well as other bone marrow derived cells. Furthermore, CXCL12regulates angiogenesis/vasculogenesis linked to tumor progression andplays a key role in seeding circulating tumor cells to metastatic sites.Besides its chemotactic functions, CXCL12 has been shown to regulatetumor cell proliferation, motility and survival (Kryczek I et al.;CXCL12 and vascular endothelial growth factor synergistically induceneoangiogenesis in human ovarian cancers; Cancer Res. 2005,65(2):465-72; Teicher B A et al.; CXCL12 (SDF-1)/CXCR4 pathway incancer; Clin Can Res. 2010, 16(11):2927-31; Domanska U M et al.; Areview on CXCR4/CXCL12 axis in oncology: no place to hide; European J ofcancer. 2013, 49(1):219-30).

In addition to CXCR7, CXCL12 binds and activates CXCR4 (alias Fusin,alias Leukocyte-derived seven-transmembrane-domain receptor; LESTR,alias D2S201E, alias seven-transmembrane-segment receptor, alias HM89,alias lipopolysaccharide-associated protein 3; Iap3, aliasLPS-associated protein 3) while CXCL11 binds and activate CXCR3 (aliasGPR9, alias CD183).

The interaction of CXCR7 and its ligands CXCL12 and CXCL11 (henceforthreferred to as the CXCR7 axis) is thus involved in guiding receptorbearing cells to specific locations in the body, particularly to sitesof inflammation, immune injury and immune dysfunction and is alsoassociated with tissue damage, the induction of apoptosis, cell growthand angiostasis. CXCR7 and its ligands are upregulated and highlyexpressed in diverse pathological situations including cancer,autoimmune disorders, inflammation, infection, transplant rejection,fibrosis and neurodegeneration.

Cancers figure among the leading causes of death worldwide. Tumors arecomprised of abnormally proliferating malignant cancer cells but also ofa functionally supportive microenvironment. This tumor microenvironmentis comprised of a complex array of cells, extracellular matrixcomponents, and signaling molecules and is established by the alteredcommunication between stromal and tumor cells. As tumors expand in size,they elicit the production of diverse factors that can help the tumor togrow such as angiogenic factors (promoting ingrowth of blood vessels) orthat can help to evade the attack of the host immune response. CXCL12 issuch an angiogenic and immuno-modulatory factor produced in tumors.

The present CXCR7 modulators may be useful, alone, or in combination incancers where the expression of the CXCL11/CXCL12 receptor CXCR7correlates with disease progression in cancer (among others in pancreascancer, pancreatic adenocarcinoma, breast cancer, hormone refractoryprostate cancer, renal cell carcinoma, cervical cancer, cervicalintra-epithelial neoplasia, papillary thyroid carcinoma, bladder cancer,Ewing's sarcoma, colon cancer, colorectal cancers, lung cancer, lungadenocarcinoma, non-small cell lung cancer, meningiomas, MALT lymphoma,cutaneous squamous cell carcinoma, neuro-endocrine tumors, nasopharyngalcarcinoma, glioblastoma multiforme, astrocytomas, gliomas,hepatocellular carcinoma, oestrogen positive breast cancer,osteosarcoma, gallbladder cancer, kidney tumors, and renal cellcarcinoma). CXCR7 is also expressed in leukemias, adenocarcinomas, brainmetastases, multiple myelomas, head and neck cancer, primary cutaneousmelanoma, melanoma, metastatic melanoma, rhabdomyosarcoma, pituitatyadenoma, oral squamous cell carcinoma, oral tumors, lymphoplasmacyticlymphoma, adult T-cell leukemia, brain tumors, esophageal squamouscancer, esophageal cancer, ovarian carcinoma, lymphoma, viral-inducedtumors, otorhinolaryngologic neoplasm, Burkitt's lymphoma, Hodgkin'slymphoma, thyroid cancers, cervical squamous cell carcinoma, endometrialcancer, neuroblastoma, gastro-intestinal cancer, lymphoproliferativedisease, acute myeloid leukemia, acute lymphoid leukemia, gastriccancer, nerve sheath tumors and choriocarcinoma, malignant pleuralmesothelioma, neurilemnoma, meningioma, diffuse large B cell lymphoma,oral leukoplakia, Kaposi sarcoma, and alveolar rhabdomyosarcoma (forreview see Sun et al.; CXCL12/CXCR4/CXCR7 Chemokine Axis and CancerProgression; Cancer Metastasis Rev. 2010, 29(4), 709-722).

The present CXCR7 modulators may be useful, alone, or in combination, indiseases where CXCR7 modulation using siRNA, shRNA, microRNAs,overexpression, CXCR7 knock-out animals, CXCR7 agonists, CXCR7antagonists, antibodies or nanobodies have been shown to alter tumorgrowth in experimental disease models as single agents, or incombination with cytotoxic therapies in including among othershepatocellular carcinoma (Xue T C et al.; Down-regulation of CXCR7inhibits the growth and lung metastasis of human hepatocellularcarcinoma cells with highly metastatic potential; Exp Ther Med. 2012,3(1):117-123; Zheng et al.; Chemokine receptor CXCR7 regulates theinvasion, angiogenesis and tumor growth of human hepatocellularcarcinoma cells; Journal of Experimental and Clinical Cancer Research.2010, 11; 29:31), Kaposi's sarcoma (Raggo C et al.; Novel cellular genesessential for transformation of endothelial cells by Kaposi'ssarcoma-associated herpesvirus; Cancer Res. 2005, 65(12):5084-95), Tcell leukemia (Jin Z et al.; CXCR7 is inducible by HTLV-1 Tax andpromotes growth and survival of HTLV-1-infected T cells; Int J Cancer.2009, 125(9):2229-35), lymphoma (Burns J M et al.; A novel chemokinereceptor for SDF-1 and I-TAC involved in cell survival, cell adhesion,and tumor development; J Exp Med. 2006, 203(9):2201-13), lungcarcinomas, breast cancer (Miao Z et al.; CXCR7 (RDC1) promotes breastand lung tumor growth in vivo and is expressed on tumor-associatedvasculature. PNAS. 2007, 104(40):15735-40), rhabdomyosarcoma (Grymula Ket al.; Overlapping and distinct role of CXCR7-SDF-1/ITAC andCXCR4-SDF-1 axes in regulating metastatic behavior of humanrhabdomyosarcomas; Int J cancer. 2010, 127(11):2554-68), prostate cancer(Wang J et al.; The role of CXCR7/RDC1 as a chemokine receptor forCXCL12/SDF-1 in prostate cancer; J biol Chem. 2008, 283(7):4283-94),pancreatic cancer (Shakir M et al.; The chemokine receptors CXCR4/CXCR7and their primary heterodimeric ligands CXCL12 and CXCL12/high mobilitygroup box 1 in pancreatic cancer growth and development: finding flow;Pancreas. 2015, 44(4):528-34), esophageal squamous cancer (Zhou S M etal.; miR-100 suppresses the proliferation and tumor growth of esophagealsquamous cancer cells via targeting CXCR7; Oncol Rep. 2016,35(6):3453-9), endometrial cancer (Long P et al.; Inhibition of CXCR4and CXCR7 for reduction of cell proliferation and invasion in humanendometrial cancer; Tumour boil. 2016, 37(6):7473-80), papillary thyroidcarcinoma (Zhang H et al.; The chemokine receptor CXCR7 is a criticalregulator for the tumorigenesis and development of papillary thyroidcarcinoma by inducing angiogenesis in vitro and in vivo; Tumour boil.2016, 37(2):2415-23), oral squamous cell carcinoma (Chen N et al.;CXCL12-CXCR4/CXCR7 axis contributes to cell motilities of oral squamouscell carcinoma; Tumour boil. 2016, 37(1):567-75), lung metastasis(Goguet-Surmenian et al.; CXCR7-mediated progression of osteosarcoma inthe lungs.; Br J Cancer. 2013, 109(6):1579-85), melanoma (McConnell A Tet al.; The prognostic significance and impact of the CXCR4/CXCR7/CXCL12axis in primary cutaneous melanoma; Br J Dermatol. 2016, doi:10.1111/bjd.14720), bladder cancer (Liu L et al.; Decreased expressionof miR-430 promotes the development of bladder cancer via theupregulation of CXCR7; Mol Med Rep. 2013, 8(1):140-6), multiple myeloma(Azab A K et al.; CXCR7-dependent angiogenic mononuclear celltrafficking regulates tumor progression in multiple myeloma; Blood.2014, 124(12):1905-14), osteosarcoma (Zhang Y et al.; Knockdown of CXCR7inhibits proliferation and invasion of osteosarcoma cells throughinhibition of the PI3K/Akt and 8-arrestin pathways; Oncol Rep. 2014,32(3):965-72), colon cancer (Wang H X et al.; Role of CXC chemokinereceptor type 7 in carcinogenesis and lymph node metastasis of coloncancer; Mol Clin Oncol. 2015, 3(6):1229-1232), grade IV astrocytomas(Walters M J et al.; Inhibition of CXCR7 extends survival followingirradiation of brain tumours in mice and rats; Br J Cancer. 2014,110(5):1179-88), head and neck cancers (Maussang D et al.; Llama-derivedsingle variable domains (nanobodies) directed against chemokine receptorCXCR7 reduce head and neck cancer cell growth in vivo; J biol Chem.2013, 288(41):29562-72), neuroblastoma (Liberman J et al.; Involvementof the CXCR7/CXCR4/CXCL12 axis in the malignant progression of humanneuroblastoma; Plos One. 2012, 7(8):e43665) and glioblastoma (Liu Y;Targeting chemokine receptor CXCR7 inhibits glioma cell proliferationand mobility; Anticancer Res. 2015, 35(1):53-64; Walters M J et al.;Inhibition of CXCR7 extends survival following irradiation of braintumours in mice and rats; Br J Cancer. 2014, 110(5):1179-88; Ebsworth Ket al.; The effect of the CXCR7 inhibitor CCX662 on survival in the ENUrat model of glioblastoma; J Clin Oncol. 2012, 30(15) e13580); to altertumor-associated blood vessels (Miao Z et al.; CXCR7 (RDC1) promotesbreast and lung tumor growth in vivo and is expressed ontumor-associated vasculature. PNAS. 2007, 104(40):15735-40); to reducetumor cell seeding (Grymula K et al.; Overlapping and distinct role ofCXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behaviorof human rhabdomyosarcomas; Int J cancer. 2010, 127(11):2554-68); toregulate leucocyte migration (Berahovich R D et al.; Endothelialexpression of CXCR7 and the regulation of systemic CXCL12 levels;Immunology. 2014, 141(1):111-22); to reduce rheumatoid arthritisclinical scores in mice with collagen induced arthritis (Watanabe K etal.; Pathogenic role of CXCR7 in rheumatoid arthritis; Arthritis Rheum.2010, 62(11):3211-20); to decrease the clinical severity of experimentalautoimmune encephalomyelitis influencing leucocytes infiltration andmicroglial chemotaxis (Cruz-Orengo L et al.; CXCR7 antagonism preventsaxonal injury during experimental autoimmune encephalomyelitis asrevealed by in vivo axial diffusivity; J Neuroinflammation. 2011, 6;8:170; Bao J et al.; CXCR7 suppression modulates microglial chemotaxisto ameliorate experimentally-induced autoimmune encephalomyelitis;Biochem Biophys Res Commun. 2016 Jan. 1; 469(1):1-7); to reduce diseaseactivity of experimental autoimmune neuritis (Brunn A et al.;Differential effects of CXCR4-CXCL12- and CXCR7-CXCL12-mediated immunereactions on murine P0106-125-induced experimental autoimmune neuritis;Neuropathol Appl Neurobiol. 2013, 39(7):772-87); to promoteremyelination in a cuprizone model, promoting oligodendroglial cellmaturation (Williams J L et al.; Targeting CXCR7/ACKR3 as a therapeuticstrategy to promote remyelination in the adult central nervous system; JExp Med. 2014, 5; 211(5):791-9; Gottle P et al.; Activation of CXCR7receptor promotes oligodendroglial cell maturation; Ann Neurol. 2010,68(6):915-24); to attenuate chronic hypoxia-induced pulmonaryhypertension (Sartina E et al.; Antagonism of CXCR7 attenuates chronichypoxia-induced pulmonary hypertension; Pediatr Res. 2012, 71(6):682-8);to induce anxiolytic-like behaviour (Ikeda Y et al.; Modulation ofcircadian glucocorticoid oscillation via adrenal opioid-CXCR7 signalingalters emotional behaviour; Cell. 2013, 5; 155(6):1323-36); to triggeran angiocrine response to initiate liver regeneration and resolvefibrosis, to promote alveolar repair and reduce lung fibrosis (Cao Z etal.; Targeting of the pulmonary capillary vascular niche promotes lungalveolar repair and ameliorates fibrosis; Nat Med. 2016; 22(2):154-62);to limit atherosclerosis reducing macrophages migration (Zhao D et al.;Pioglitazone Suppresses CXCR7 Expression To Inhibit Human MacrophageChemotaxis through Peroxisome Proliferator-Activated Receptor γ;Biochemistry. 2015, 17; 54(45):6806-14; Ma W. et al.; Atorvastatininhibits CXCR7 induction to reduce macrophage migration. BiochemPharmacol. 2014, 1; 89(1):99-108); and to improve beneficial effects ofmesenchymal stem cells based therapies for renal ischemia/reperfusioninjury (Liu H et al.; The role of SDF-1-CXCR4/CXCR7 axis in thetherapeutic effects of hypoxia-preconditioned mesenchymal stem cells forrenal ischemia/reperfusion injury; Plos One. 2012, 7(4):e34608).

Furthermore, CXCR7 has been proposed to be involved in cardiac stem cellmigration (Chen D et al.; Crosstalk between SDF-1/CXCR4 and SDF-1/CXCR7in cardiac stem cell migration; Sci Rep. 2015, 5:16813), chronicallograft vasculopathy (Thomas M N et a.; SDF-1/CXCR4/CXCR7 is pivotalfor vascular smooth muscle cell proliferation and chronic allograftvasculopathy; Transpl Int. 2015, 28(12):1426-35), inflammatory boweldisease (Werner L et al.; Involvement of CXCR4/CXCR7/CXCL12 Interactionsin Inflammatory bowel disease; Theranostics. 2013, 3(1):40-6), chronicrhinosinusitis (Patadia M et al.; Evaluation of the presence of B-cellattractant chemokines in chronic rhinosinusitis; Am J Rhinol Allergy.2010, 24(1):11-6), human pulmonary vascular diseases (Rafii S et al.;Platelet-derived SDF-1 primes the pulmonary capillary vascular niche todrive lung alveolar regeneration; Nat Cell Biol. 2015, 17(2):123-36) anddevelopment of severe preeclampsia (Lu J et al.; CXCR4, CXCR7, andCXCL12 are associated with trophoblastic cells apoptosis and linked topathophysiology of severe preeclampsia.; Exp Mol Pathol. 2016,100(1):184-91). In addition to the above mentioned diseases CXCR7modulators may be useful in the treatment of renal allograft rejection,systemic lupus erythematosus, osteoarthritis, pulmonary vasculardiseases, acute renal failure, ischemia, chronic allograft rejection,acute coronary syndrome, injured central nervous system; hyperlipidemia,HSCs transplantation, cerebral ischemia, hypertension, pulmonaryhypertension, Shiga-toxin-associated heomolytic uremic syndrome,HIV/AIDS; acute lung injury, asthma, cirrhosis, stress-relateddisorders, proliferative diabetic retinopathy, West Nile virusencephalitis, vascular injury and pulmonary fibrosis.

Mechanistically, recent studies have provided increasing evidence thatactivation of the CXCL12 pathway is a potential mechanism of tumorresistance to both conventional therapies and biological agents viamultiple complementary actions: (i) by directly promoting cancer cellsurvival, invasion, and the cancer stem and/or tumor-initiating cellphenotype; (ii) by recruiting “distal stroma” (i.e., myeloid bonemarrowderived cells) to facilitate immune-suppression, tumor recurrence,and metastasis; and (iii) by promoting angiogenesis directly or in aparacrine manner (Duda D G et al: CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathwayinhibition: an emerging sensitizer for anticancer therapies?; ClinCancer Res; 2011, 17(8); 2074-80) recently discussed preclinical andclinical data that support the potential use of anti-CXCL12 agentsincluding CXCR7 modulators as sensitizers to currently availabletherapies in cancer treatments. In addition, the enhancement in CXCR7expression on endothelium seems to be critical for the inflammatoryinfiltration in autoimmune diseases. CXCL12 and CXCL11 are key ligandsin inflammatory immune response: (i) by acting on cell migration, oncell adhesion and cell survival (Kumar R et al.; CXCR7 mediated Giαindependent activation of ERK and Akt promotes cell survival andchemotaxis in T cells; Cell Immunol. 2012, 272(2):230-41); (ii) bydriving differentiation and polarization of cell i.e., macrophages (MaW. et al.; Atorvastatin inhibits CXCR7 induction to reduce macrophagemigration. Biochem Pharmacol. 2014, 1; 89(1):99-108), CD4+ T cells/ZoharY et al.; CXCL11-dependent induction of FOXP3-negative regulatory Tcells suppresses autoimmune encephalomyelitis; J Clin Invest. 2014,124(5):2009-22), oligodendrocytes progenitors (Gottle P et al.;Activation of CXCR7 receptor promotes oligodendroglial cell maturation;Ann Neurol. 2010, 68(6):915-24); (iii) by participating in homingprocesses (Lewellis S W et al.; Precise SDF1-mediated cell guidance isachieved through ligand clearance and microRNA-mediated decay. J CellBiol. 2013, 4; 200(3):337-55). Therefore, targeting CXCR7 and thusregulating the level of its ligands would have a decisive role in thepathogenesis of a wide variety of autoimmune and inflammatory diseases.Sanchez-Martin et al (Sanchez-Martin et al.; CXCR7 impact on CXCL12biology and disease; Trends Mol Med. 2013, 19(1):12-22) recentlydiscussed dysregulation of CXCR7 in disease and highlighted the factthat this receptor is an attractive therapeutic target for the treatmentof autoimmune diseases and inflammation.

Thus, the present CXCR7 antagonists may be useful, alone, or incombination with with one or more therapeutic agents and/or chemotherapyand/or radiotherapy and/or immunotherapy; in particular in combinationwith chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors,immunotherapy such as especially PD1 and/or PDL1 blockade and/or CTLA4blockade, or other targeted therapies; for the prevention/prophylaxis ortreatment of cancers such as carcinomas; adenocarcinomas; neuroendocrinetumors; skin cancer including melanoma and metastatic melanoma; lungcancer including non-small cell lung cancer; metastatic cancer; lungmetastasis; bladder cancer including urinary bladder cancer; urothelialcell carcinoma; renal carcinomas including renal cell carcinoma;metastatic renal cell carcinoma, metastatic renal clear cell carcinoma;gastro-intestinal cancers including colon carcinoma, colorectal adenoma,colorectal adenocarcinoma, colorectal cancer, metastatic colorectalcancer, familial adenomatous polyposis (FAP), oesophageal cancer, oralsquamous cell carcinoma; gastric cancer, gallbladder cancer,cholangiocarcinoma, hepatocellular carcinoma; pancreatic cancer such aspancreatic adenocarcinoma or pancreatic ductal (adeno)carcinoma;endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma;prostate cancer including castrate-resistant prostate cancer; braintumors including brain metastases, malignant gliomas, glioblastomamultiforme, medulloblastoma, meningiomas; breast cancer including triplenegative breast carcinoma; oral tumors;

nasopharyngeal tumors; thoracic cancer; head and neck cancer; leukemiasincluding acute myeloid leukemia, adult T-cell leukemia; thyroidcarcinoma including papillary thyroid carcinoma; choriocarcinoma;Ewing's sarcoma; osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma;lymphoma including Burkitt's lymphoma, Hodgkin's lymphoma, MALTlymphoma; primary intra-ocular B-Cell lymphoma, multiple myelomas andvirally induced tumors; and diseases involving CXCR7 and/or CXCL12and/or CXCL11 mediated metastasis, chemotaxis, cell adhesion,trans-endothelial migration, cell proliferation and/or survival.

Specifically, the potential role of CXCR7 in brain tumors, malignantglioma and in glioblastoma multiforme is known from the literature.Modulators of the CXCL12 pathway including CXCR7 modulators have beenmentioned as potential therapeutic agents for treating brain cancer incombination with chemotherapeutic agents or radiotherapy. For example,Hattermann et al (Hattermann et al.; The chemokine receptor CXCR7 ishighly expressed in human glioma cells and mediates antiapoptoticeffects; Cancer research 2010, 70 (8):3299-3308) teach that CXCL12“stimulation prevented camptothecin- and temozolomide-induced apoptosisand that a CXCR7 antagonist reduced the antiapoptotic effect of CXCL12”.The authors concluded that “CXCR7 is a functional receptor for CXCL12 inastrocytomas/glioblastomas and mediates resistance to drug-inducedapoptosis”. Furthermore, Hattermann et al (Hattermann et al.; CXCL12mediates apoptosis resistance in rat C6 glioma cells; Oncol Rep. 2012,27: 1348-1352) teach that “CXCL12 abrogates the antiproliferative effectof temozolomide”. The authors also teach that this effect could bealmost completely abolished by a CXCR7 specific antagonist, “indicatingthat the anti-apoptotic effect of CXCL12 is mainly mediated via CXCR7”.Ebsworth et al (Ebsworth et al.; Neuro Oncol (2013) 15 (suppl3):iii37-iii61. ET-023) teach that a CXCR7 antagonist significantlyprolongs survival when administered in combination with radiotherapy ina rat model of glioblastoma. This finding is supported by other studies(e.g. Ebsworth K et al.; The effect of the CXCR7 inhibitor CCX662 onsurvival in the ENU rat model of glioblastoma; J Clin Oncol. 2012,30(15) e13580; Walters M J et al.; Inhibition of CXCR7 extends survivalfollowing irradiation of brain tumours in mice and rats; Br J Cancer.2014, 110(5):1179-88) disclosing that in vivo inhibition of CXCR7 inconcert with radiotherapy results in a significant extension of survivaltime in another rat model of glioblastoma. In addition, Liu S C et al(Liu S C et al.; Neuro-Oncology 2014; 16(1):21-28) teach that inhibitionof CXCL12 after irradiation inhibits tumor recurrence in autochtonousbrain tumors in rats. Liu S C et al (Liu S C et al.; Blockade of SDF-1after irradiation inhibits tumor recurrences of autochthonous braintumors in rats; Neuro Oncol. 2013, 16(1):21-8) also teach thatinhibition of CXCL12 in a brain metastasis model after irradiationproduced a marked inhibition of tumor growth and prolongation oflifespan compared to irradiation alone. Calatozzolo C et al (CalatozzoloC et al.; Expression of the new CXCL12 receptor, CXCR7, in gliomas;Cancer Biol Ther. 2011, 11(2), 1-12) teach in in vitro experiments thatCXCR7 antagonists showed complete inhibition of glioma proliferation.

Specifically, a role for CXCR7 in pancreas tumors, has been described inthe literature. Shakir et al. (Shakir M et al.; The chemokine receptorsCXCR4/CXCR7 and their primary heterodimeric ligands CXCL12 andCXCL12/high mobility group box 1 in pancreatic cancer growth anddevelopment: finding flow; Pancreas. 2015, 44(4):528-34) observed thatCXCR4 and CXCR7, upon interaction with CXCL12, activate downstreamprotein kinases that promote a more aggressive behaviour. Moreover, theexpression of CXCR7 and CXCI12 correlates with tumors histologicalgrades (Liu Z et al.; Expression of stromal cell-derived factor 1 andCXCR7 ligand receptor system in pancreatic adenocarcinoma. World J SurgOncol. 2014, 12:348). These findings were confirmed by Heinrich E L etal. (Heinrich E L et al.; Chemokine CXCL12 activates dual CXCR4 andCXCR7-mediated signaling pathways in pancreatic cancer cells; J TranslMed. 2012, 10:68). Therefore, CXCR7 modulators may be useful in thetreatment of pancreas cancers.

CXCR7 modulators may also be useful in the treatment of papillarythyroid carcinoma. Liu Z et al. (Liu Z et al.; The involvement of CXCR7in modulating the progression of papillary thyroid carcinoma; J SurgRes. 2014, 191(2):379-88) described that CXCR7 messenger RNA and proteinlevels were markedly increased in papillary thyroid carcinoma andcorrelated with tumor progression. CXCR7 could regulate proliferation,cell cycle, apoptosis, invasion, and the expression of cell cycleregulatory proteins involved in the S-G2 phase transition. Knockdown ofCXCR7 in papillary thyroid carcinoma cells suppressed cell proliferationand invasion, induced S phase arrest, and promoted apoptosis. Zhang H etal further demonstrated that CXCR7 affects the growth of papillarythyroid carcinoma cells and participates in the tumorigenesis ofpapillary thyroid carcinoma, probably through regulating angiogenesis bythe proangiogenic VEGF or IL-8. (Zhang H et al.; The chemokine receptorCXCR7 is a critical regulator for the tumorigenesis and development ofpapillary thyroid carcinoma by inducing angiogenesis in vitro and invivo; Tumor Biol. 2016, 37(2):2415-23). The expression and function ofthe CXCR7 axis in thyroid cancer was confirmed by Zhu X et al. (by Zhu Xet al.; Expression and function of CXCL12/CXCR4/CXCR7 in thyroid cancer;Int J Oncol. 2016, 48(6):2321-9)

CXCR7 modulators may also be useful in the treatment of lung cancer:Using a combination of overexpression and RNA interference, Miao Z et al(Miao Z et al.; CXCR7 (RDC1) promotes breast and lung tumor growth invivo and is expressed on tumor-associated vasculature. PNAS. 2007,104(40):15735-40) established that CXCR7 promotes growth of tumorsformed from breast and lung cancer cells and enhances experimental lungmetastases. Iwakiri S et al. (Iwakiri S et al.; Higher expression ofchemokine receptor CXCR7 is linked to early and metastatic recurrence inpathological stage I nonsmall cell lung cancer; Cancer. 2009,115(11):2580-93) observed that higher expression of CXCR7 is linked toearly and metastatic recurrence in pathological stage I non small celllung cancer.

CXCR7 modulators may also be useful in the treatment of hepatocellularcarcinoma: it was reported that CXCR7 expression is increased inhepatocellular carcinoma tissues. Knockdown of CXCR7 expressionsignificantly inhibited hepatocellular carcinoma cells invasion,adhesion and angiogenesis. In addition, down-regulation of CXCR7expression lead to a reduction of tumor growth in a xenograft model ofhepatocellular carcinoma (Zheng K et al.; Chemokine receptor CXCR7regulates the invasion, angiogenesis and tumor growth of humanhepatocellular carcinoma cells; J Exp Clin Cancer Res. 2010, 29:31).Monnier J et al. also observed in a cohort of 408 human hepatocellularcarcinoma, that CXCR7 was significantly higher in tumours compared tonormal liver controls (Monnier J et al.; CXCR7 is up-regulated in humanand murine hepatocellular carcinoma and is specifically expressed byendothelial cells; Eur J Cancer. 2012, 48(1):138-48).Immunohistochemical staining on human hepatocellular carcinoma sectionsconfirmed that CXCR7 expression was much higher in cancer tissues. UsingRNAi of CXCR7 in an hepatocellular carcinoma cell line, Xue T C et allobserved that CXCR7 dowregulation decreased the growth of tumors and thenumber of lung metastases in nude mice. Moreover, tissue microarrayshowed that HCCs with high expression of CXCR7 were prone to metastasizeto the lung. Down-regulation of CXCR7 inhibits the growth and lungmetastasis of human hepatocellular carcinoma cells with highlymetastatic potential (Xue T C et al.; Down-regulation of CXCR7 inhibitsthe growth and lung metastasis of human hepatocellular carcinoma cellswith highly metastatic potential; Exp Ther Med. 2012, 3(1):117-123).

CXCR7 modulators may also be useful in the treatment of metastatic coloncancer: Guillemot et al. (Guillemot et al.; CXCR7 receptors facilitatethe progression of colon carcinoma within lung not within liver; Br JCancer. 2012, 107(12):1944-9) observed that following injection ofcolorectal cancer cells, mice treated with a CXCR7 antagonists exhibiteda significant reduction in lung metastasis. Wang H X et al studied CXCR7expression in colon cancer specimen and observed that CXCR7 levels weresignificantly higher in colon tumors compared with those in normal colontissue. In addition, lymph node metastatic colon tumors exhibitedsignificantly higher CXCR7 expression compared with non-metastatictumors (Wang H X et al.; Role of CXC chemokine receptor type 7 incarcinogenesis and lymph node metastasis of colon cancer; Mol ClinOncol. 2015, 3(6):1229-1232).

CXCR7 modulators may also be useful in the treatment of head and neckcancer: A nanobody directed against CXCR7 reduced head and neck cancergrowth in vivo (Maussang D et al.; Llama-derived single variable domains(nanobodies) directed against chemokine receptor CXCR7 reduce head andneck cancer cell growth in vivo; J biol Chem. 2013, 288(41):29562-72).Moreover, the same authors analysed a wide variety of tumor biopsies andshowed high expression of CXCR7 in head and neck cancer.

CXCR7 is also reported to be expressed in brain metastases (Salmaggi etal.; CXCL12, CXCR4 and CXCR7 expression in brain metastases. Cancer BiolTher.2009, 8:17, 1-7). The authors concluded that the CXCL12/CXCR4/CXCR7pathway could be an interesting target for further researchesinvestigating the role of these molecules in invasion and proliferationof metastatic cells.

Specifically, the impact of CXCR7 on inflammatory demyelinating diseasesis known from the literature. CXCR7 is expressed in various regionsthroughout the adult mouse brain and its expression is upregulated inmouse model for multiple sclerosis (Banisadr G et al.; Pattern of CXCR7Gene Expression in Mouse Brain Under Normal and Inflammatory Conditions;J Neuroimmune Pharmacol. 2016 March; 11(1):26-35). Altered expressionpatterns of CXCL12 at the blood-brain barrier (BBB) is involved inmultiple sclerosis and correlate with severity of the disease(McCandless E E et al.; Pathological expression of CXCL12 at theblood-brain barrier correlates with severity of multiple sclerosis; Am JPathol. 2008, 172(3):799-808). CXCR7 antagonism have been shown to beeffective in experimental autoimmune encephalomyelitis in mice. Thoserecent studies strongly implicate CXCR7 as a disease-modifying moleculein multiple sclerosis via complementary mechanisms: (i) by facilitatingleucocytes entry into the perivascular space via CXCL12 redistributionat the BBB (Cruz-Orengo L et al.; CXCR7 antagonism prevents axonalinjury during experimental autoimmune encephalomyelitis as revealed byin vivo axial diffusivity; J Neuroinflammation. 2011, 6; 8:170;Cruz-Orengo L et al.; CXCR7 influences leukocyte entry into the CNSparenchyma by controlling abluminal CXCL12 abundance duringautoimmunity; J Exp Med. 2011, 14; 208(2):327-39) and regulating theCXCR4-mediated activation of integrins (Hartmann T N et al.; A crosstalkbetween intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggeredintegrin activation but not in chemokine-triggered motility of human Tlymphocytes and CD34+ cells; J Leukoc Biol. 2008; 84(4):1130-40) (ii) bydirect effect on microglial chemotaxis (Bao J et al.; CXCR7 suppressionmodulates microglial chemotaxis to ameliorate experimentally-inducedautoimmune encephalomyelitis; Biochem Biophys Res Commun. 2016 Jan. 1;469(1):1-7) (iii) by promoting remyelination via increase levels ofCXCL12 enhancing CXCR4-mediated oligodendrocytes progenitor cellsmaturation (Williams J L et al.; Targeting CXCR7/ACKR3 as a therapeuticstrategy to promote remyelination in the adult central nervous system; JExp Med. 2014, 5; 211(5):791-9; Gottle P et al.; Activation of CXCR7receptor promotes oligodendroglial cell maturation; Ann Neurol. 2010,68(6):915-24). Thus CXCR7 antagonism could therapeutically preventinflammation and enhance myelin repair in the demyelinated adult CNS.

Moreover, CXCR7 antagonism have been shown to be effective in a mousemodel for Guillain-Barré syndrome. Indeed, Brunn et al (Brunn A et al.;Differential effects of CXCR4-CXCL12- and CXCR7-CXCL12-mediated immunereactions on murine P0106-125-induced experimental autoimmune neuritis;Neuropathol Appl Neurobiol. 2013, 39(7):772-87) teach that“antagonization of CXCR7 reduced disease prevalence to 75% andimpressively minimized disease activity” in a mouse model ofexperimental autoimmune neuritis. The authors conclude that“CXCR7/CXCL12-interaction is a gatekeeper for pathogenic cells”.

Specifically, the potential role of CXCR7 in rheumatoid arthritis isknown from the literature. CXCR7 is reported to be expressed onendothelial cells in the synovium. Also, elevated levels of CXCL12 andCXCL11 mRNA were found in synovial tissue of rheumatoid arthritispatients (Ueno et al.; The production of CXCR3-agonistic chemokines bysynovial fibroblasts from patients with rheumatoid arthritis; RheumatolInt. 2005, 25(5):361-7). CXCL12 was shown to play a central role in CD4+T cell and monocytes accumulation in the synovium (Nanki T et al.;Stromel cell-derived factor-1-CXC chemokine receptor 4 interactions playa central role in CD4+ T cell accumulation in rheumatoid arthritissynovium; J Immunol. 2000, 165(11):6590-8; Blades M C et al.; Stromelcell-derived factor 1 (CXCL12) induces monocyte migration into humansynovium transplanted onto SCID Mice; Arthritis Rheum. 2002 March;46(3):824-36). In addition CXCL12 participates in the rheumatoidarthritis process via its pro-angiogenic functions and its action onosteoclast recruitment and differentiation. Therefore, modulators of theCXCL12 pathway including CXCR7 modulators have been proposed aspotential therapeutic agents to treat rheumatoid arthritis. Villalvillaet al (Villalvilla A et al.; SDF-1 signaling: a promising target inrheumatic diseases; Expert Opin Ther Targets. 2014, 18(9):1077-87)recently discussed preclinical and clinical data that support thepotential use of anti-CXCL12 agents in rheumatoid arthritis treatments.Watanabe et al (Watanabe K et al.; Pathogenic role of CXCR7 inrheumatoid arthritis; Arthritis Rheum. 2010, 62(11):3211-20) teach thata CXCR7 inhibitor prophylactically and therapeutically reduces diseaseclinical signs and angiogenesis in a mouse collagen-induced arthritismodel.

Specifically, CXCR7 is involved in several inflammatory disorders. Forexample, CXCL12 and CXCL11 are involved in chronic lung inflammatoryprocesses (Petty J M et al.; Pulmonary stromal-derived factor-1expression and effect on neutrophil recruitment during acute lunginjury; J Immunol. 2007, 178(12):8148-57; Porter J C et al.; Polarizedlocalization of epithelial CXCL11 in chronic obstructive pulmonarydisease and mechanisms of T cell egression; J Immunol. 2008,180(3):1866-77). CXCL12 was found upregulated in the lung in both humansand animals models (Phillips R J et al.; Circulating fibrocytes trafficto the lungs in response to CXCL12 and mediate fibrosis; J Clin Invest.2004, 114(3):438-46). Anti-CXCL12 agents have been shown to attenuatelung inflammation and airway hyppereactivity in asthma models (GasparikV et al.; Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand PreventInflammatory Reactions in an Asthma Model in Vivo; ACS Med Chem Lett.2012 Jan. 12; 3(1):10-4; Lukacs N W et al.; AMD3100, a CXCR4 antagonist,attenuates allergic lung inflammation and airway hyperreactivity; Am JPathol. 2002, 160(4):1353-60). Petty et al. (Petty J M et al.; Pulmonarystromal-derived factor-1 expression and effect on neutrophil recruitmentduring acute lung injury. J Immunol. 2007, 178(12):8148-57) teach thatCXCL12 blockade attenuates late neutrophilia in the acute lung injury inmice. Cao et al (Cao Z et al.; Targeting of the pulmonary capillaryvascular niche promotes lung alveolar repair and ameliorates fibrosis;Nat Med. 2016; 22(2):154-62) teach that CXCR7 modulator after lunginjury “promotes alveolar repair and reduces fibrosis” in a mouse modelof lung fibrosis. CXCL12 and CXCL11 are also reported to be upregulatedin Inflammatory bowel diseases (Koelink P J et al.; Targeting chemokinereceptors in chronic inflammatory diseases: an extensive review;Pharmacol Ther. 2012, 133(1):1-18). CXCR7 was found upregulated onperipheral blood T cells in Inflammatory bowel diseases (Werner L etal.; Reciprocal regulation of CXCR4 and CXCR7 in intestinal mucosalhomeostasis and inflammatory bowel disease; J Leukoc Biol. 2011,90(3):583-90). The author hypothetise that “the increased expression ofCXCR7 in the peripheral blood of Inflammatory bowel diseases patientscould foster increased influx of T cells to sites of mucosalinflammation” (Werner L et al.; Involvement of CXCR4/CXCR7/CXCL12Interactions in Inflammatory bowel disease; Theranostics. 2013,3(1):40-6). In mouse models for Inflammatory bowel disease, modulatorsof the CXCL12 pathway could decrease infiltration of T cells and reducetissue damage (Mikami S et al.; Blockade of CXCL12/CXCR4 axisameliorates murine experimental colitis; J Pharmacol Exp Ther. 2008,327(2):383-92; Xia X M et al.; CXCR4 antagonist AMD3100 modulatesclaudin expression and intestinal barrier function in experimentalcolitis; PLoS One. 2011, 6(11):e27282).

Elevated levels of CXCL12 and CXCL11 have also been found in lesionalpsoriatic skin (Chen S C et al.; Expression of chemokine receptor CXCR3by lymphocytes and plasmacytoid dendritic cells in human psoriaticlesions; Arch Dermatol Res. 2010, 302(2):113-23; Zgraggen S et al.; Animportant role of the SDF-1/CXCR4 axis in chronic skin inflammation;PLoS One. 2014, 9(4):e93665). Zgraggen et al teach that blockade ofCXCL12 improved the course of chronic skin inflammation in two differentmodels of psoriasis-like skin inflammation.

Several other auto-immune disorders like systemic lupus erythematosus(SLE) display altered CXCR7/CXCR4 expression correlated with an impairedCXCL12-promoted migration of SLE B cells (Biajoux V et al.; Expressionof CXCL12 receptors in B cells from Mexican Mestizos patients withsystemic Lupus erythematosus; J Transl Med. 2012, 18; 10:251). Inaddition, CXCL12 was significantly up-regulated in the nephritic kidneysin multiple murine models of lupus. Wang et al. (Wang A et al.;CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis oflupus; J Immunol. 2009, 182(7):4448-58) teach that acting on the CXCL12axis is a good therapeutic target in lupus, as a CXCR4 antagonistsignificantly ameliorates the disease, prolonging survival and reducingnephritis and lymphoproliferation.

CXCR7 modulators may also be useful in the treatment of fibrosis: Cao Zet al (Cao Z. et al; Targeting of the pulmonary capillary vascular nichepromotes lung alveolar repair and ameliorates fibrosis. Nat Med. 2016,22(2):154-62) demonstrated that the administration of a CXCR7 modulatorafter lung injury promotes alveolar repair and reduces fibrosis. A rolefor CXCR7 in liver fibrosis was also described (Ding B S et al.;Divergent angiocrine signals from vascular niche balance liverregeneration and fibrosis; Nature. 2014, 505(7481):97-102).

The biological properties of CXCR7 modulators also include, but are notlimited to, any physiological function and/or cellular function linkedand/or controlled by its ligands CXCL11, CXCL12, BAM22 and its relatedpeptides. Hence, CXCL12 depletion sensitizes cancer cells tochemotherapy in vivo and CXCL12 treatment blocks colonic carcinomametastasis (Duda et al.; CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathwayinhibition: an emerging sensitizer for anticancer therapies?; Clin.Cancer Res. 2011 17(8) 2074-2080; Naumann et al.; CXCR7 function as ascavenger for CXCL12 and CXCL11; Plos One. 2010, 5(2) e9175). CXCR7 isalso a receptor for CXCL11 (alias small inducible cytokine subfamily b,member 11; scyb11, alias interferon-gamma-inducible protein 9; ip9,alias small inducible cytokine subfamily b, member 9b; scyb9b) andtherefore modulators of CXCR7 activity can also be used in indicationswith CXCL11-associated pathology (Rupertus K et al.; Interaction of thechemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumorangiogenesis of colorectal cancer; Clin Exp Metastasis. 2014,31(4):447-59; Zohar Y et al.; CXCL11-dependent induction ofFOXP3-negative regulatory T cells suppresses autoimmuneencephalomyelitis; J Clin Invest. 2014, 124(5):2009-22; Antonelli A etal.; Increase of interferon-γ inducible CXCL9 and CXCL11 serum levels inpatients with active Graves' disease and modulation by methimazoletherapy; Thyroid. 2013, 23(11):1461-9). CXCR7 functions also as areceptor for the opioid peptide BAM22 and its related peptides (peptideE, peptides BAM12, BAM14, BAM18) and therefore modulators of CXCR7activity possibly may also be used in indications with opioid peptidesassociated pathologies (Ikeda et al.; Modulation of circadianglucocorticoid oscillation via adrenal opioid-CXCR7 signaling altersemotional behaviour; Cell. 2013, 155, 1323-1336). CXCR7 has also beenshown to function as a scavenger receptor for CXCI11 and CXCL12. Thus,CXCR7 targeting has been shown to alter CXCI11 and CXCL12 localconcentration leading to a deregulation of the CXCI11 and CXCL12concentration gradients.

Certain isoxazole compounds which are SMYD protein blockers are knownfrom WO2016/040515, wherein in the compounds of WO2016/040515, theisoxazole ring is substituted with certain (cyclo-)alkyl substituentsinstead of the present phenyl substituent Ar²; and the piperidine moietydoes not carry a carboxamide substituent R¹—CO—. Certain pyrrolecompounds are known as antibacterial agents from WO2006/087543,WO2005/026149 and J. Med. Chem 2014, 57(14), 6060-6082. Cyclic diaminesas Factor Xa inhibitors are known from WO2005/032490. WO2004/050024discloses pyrrolidine compounds as chemokine receptor modulators.

The present invention provides novel trans-3,4-di-substituted piperidinederivatives of formula (I) which are modulators of the CXCR7 receptor,i.e. they act as CXCR7 receptor antagonists, and are useful for theprevention or treatment of diseases which respond to the activation ofthe CXCL12 receptors and/or CXCL11 receptors, especially cancer. In theprevention or treatment of cancers the compounds of formula (I) may alsobe used in combination with one or more chemotherapy agents and/orradiotherapy and/or targeted therapy.

1) A first aspect of the invention relates to novel piperidinederivatives of formula (I);

whereinthe two substituents of the piperidine ring: R¹—CO— and —NH—CO—Ar¹—Ar²,are in relative trans-configuration (i.e. the relative configuration ofthe two chiral carbon atoms in position 3 and 4 of the piperidine ringis (3R*,4R*));Ar¹ represents a 5-membered heteroarylene group (especially a 5-memberedheteroarylene containing one to a maximum of three heteroatoms, eachindependently selected from oxygen, nitrogen, and sulfur; notablyoxazol-diyl, isoxazol-diyl, oxadiazol-diyl, triazol-diyl,isothiazol-diyl, or thiadiazol-diyl), wherein the —NH—CO— group and Ar²are attached in meta arrangement to ring atoms of Art; wherein said5-membered heteroarylene is unsubstituted, or mono-substituted with RAM;wherein R^(Ar1) represents (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy (especially said 5-memberedheteroarylene is unsubstituted);Ar² represents phenyl (preferred) or 6-membered heteroaryl; wherein saidphenyl or 6-membered heteroaryl independently is mono-, di- ortri-substituted, wherein the substituents are independently selectedfrom fluoro, chloro, methyl, cyano, methoxy, or (C₁)fluoroalkyl;

-   -   [notably one or two of said substituents is/are independently        selected from fluoro, chloro, and methyl, and the remaining, if        present, is/are fluoro; especially Ar² represents phenyl which        is mono-, di- or tri-substituted, wherein the substituents are        independently fluoro or chloro; in particular Ar² represents        phenyl which is mono-, di- or tri-substituted with fluoro];        R¹ represents R^(N1)R^(N2)N—, wherein    -   R^(N1) represents        -   hydrogen;        -   (C₁₋₆)alkyl (especially methyl, ethyl, isopropyl, isobutyl,            tert.-butyl, 1,2,2-trimethyl-propyl);        -   (C₁₋₆)alkyl which is mono-substituted with            -   hydroxy;            -   (C₁₋₃)alkoxy (especially methoxy, ethoxy);            -   2-hydroxy-ethoxy;            -   —CO—NH₂;            -   —SO₂—(C₁₋₃)alkyl (especially methanesulfonyl);            -   cyano;            -   (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy);            -   —NR^(N3)R^(N4), wherein R^(N3) and R^(N4) independently                represent hydrogen or (C₁₋₄)alkyl (especially                —NR^(N3)R^(N4) represents dimethylamino); (especially                such group R^(N1) being mono-substituted (C₁₋₆)alkyl is                2-hydroxy-ethyl, 2-hydroxy-1-methyl-ethyl,                2-hydroxy-1,1-dimethyl-ethyl, 2-methoxy-ethyl,                3-methoxy-propyl, 2-ethoxy-ethyl,                2-ethoxy-1-methyl-ethyl, 2-methoxy-1,1-dimethyl-ethyl,                3-methoxy-1,1-dimethyl-propyl,                2-(2-hydroxy-ethoxy)-ethyl, carbamoyl-methyl,                2-methanesulfonyl-1,1-dimethyl-ethyl,                1-cyano-1-methyl-ethyl, 2-dimethylamino-ethyl,                2-trifluoromethoxy-ethyl);        -   (C₂₋₆)alkynyl (especially 1-methyl-prop-2-ynyl);        -   (C₂₋₅)fluoroalkyl (especially 2-fluoro-ethyl,            2,2-difluoro-ethyl, 2-fluoro-1-methyl-ethyl,            2-fluoro-1,1-dimethyl-ethyl, 2,2-difluoro-1-methyl-ethyl,            3,3,3-trifluoro-1,1-dimethyl-propyl);        -   (C₁₋₄)alkoxy (especially methoxy);        -   2-(2-oxo-pyrrolidin-1-yl)-ethyl;        -   a group -L¹-Cy¹; wherein            -   L¹ represents a direct bond, —(C₁₋₃)alkylene-, or                —(C₃₋₅)cycloalkylene-; and            -   Cy¹ represents (C₃₋₆)cycloalkyl; wherein said                (C₃₋₆)cycloalkyl optionally contains one ring oxygen                atom; wherein said (C₃₋₆)cycloalkyl independently is                unsubstituted; or mono-substituted with fluoro, methyl,                hydroxy, —CO—(C₁₋₄)alkoxy, or cyano; or di-substituted                with fluoro, or tri-substituted with methyl and two                fluoro;        -   (especially such group -L¹-Cy¹ is cyclopropyl, cyclopentyl,            1-methyl-cyclopropyl, 1-methyl-cyclobutyl,            1-cyclopropyl-cyclopropan-1-yl, 1-cyclobutyl-ethyl,            3-methyl-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl-methyl,            tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2-yl-ethyl,            oxetan-3-yl-methyl, 3,3-difluoro-1-methyl-cyclobutyl,            1-(ethoxycarbonyl)-cyclopropyl, or 1-cyano-cyclobutyl);        -   a group -L²-Ar³, wherein            -   L² represents a direct bond; —(C₁₋₄)alkylene-;                *—(C₃₋₅)cycloalkylene-(C₀₋₂)alkylene- wherein said                (C₃₋₅)cycloalkylene optionally contains one ring oxygen                atom, wherein the asterisk indicates the bond to which                Ar³ is attached; *—(C₁₋₂)alkylene-(C₃₋₅)cycloalkylene-                wherein said (C₃₋₅)cycloalkylene optionally contains one                ring oxygen atom, wherein the asterisk indicates the                bond to which Ar³ is attached; or —(C₁₋₃)alkylene- which                is mono-substituted with hydroxy, trifluoromethyl, or                —CO—(C₁₋₄)alkoxy; and            -   Ar³ represents phenyl, or 5- or 6-membered heteroaryl;                wherein said phenyl or 5- or 6-membered heteroaryl                independently is unsubstituted, or mono-, or                di-substituted; wherein the substituents are                independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,                halogen, hydroxy, (C₁₋₃)fluoroalkyl, or                (C₁₋₃)fluoroalkoxy; wherein, in case Ar³ represents                6-membered heteroaryl which is pyridyl or pyrimidinyl,                such pyridyl or pyrimidinyl may additionally be present                in form of the respective N-oxide (for avoidance of                doubt, it is understood that the term 6-membered                heteroaryl comprises the groups 1-oxy-pyridinyl, and                1-oxy-pyrimidinyl);        -   (especially such group -L²-Ar³ is phenyl, benzyl,            1-phenyl-ethyl, 2-phenyl-ethyl, 2-(2-chloro-phenyl)-ethyl,            2-(4-fluoro-phenyl)-ethyl, 2-(2-methyl-phenyl)-ethyl,            2-(3-methyl-phenyl)-ethyl, 2-(4-methyl-phenyl)-ethyl,            2-(2-methoxy-phenyl)-ethyl, 2-phenyl-propyl,            2-hydroxy-1-phenyl-ethyl, 2-hydroxy-2-phenyl-ethyl,            2-phenyl-cyclopropyl; or 1-(3-bromo-phenyl)-ethyl,            1-phenyl-cyclopropyl, 1-phenyl-cyclobutyl,            2-phenyl-cyclobutyl, 1-(3-chloro-phenyl)-cyclopropyl,            1-(4-fluoro-phenyl)-cyclopropyl,            1-(3-fluoro-phenyl)-cyclopropyl,            1-(2-fluoro-phenyl)-cyclopropyl,            1-(2-methyl-phenyl)-cyclopropyl,            1-(2-hydroxy-phenyl)-cyclopropyl,            1-(2-methoxy-phenyl)-ethyl,            2-methyl-2-(2-chloro-phenyl)-propyl,            1-(4-chloro-phenyl)-cyclopropyl-methyl,            3-(3-chloro-phenyl)-oxetan-3-yl,            3-(4-fluoro-phenyl)-oxetan-3-yl,            3-(phenyl)-oxetan-3-yl-methyl, 3-(benzyl)-oxetan-3-yl,            1-(2-methoxy-phenyl)-cyclopropyl,            1-(3-methoxy-phenyl)-cyclopropyl,            1-(2-trifluoromethyl-phenyl)-cyclopropyl,            2-ethoxy-2-oxo-1-phenylethyl; or        -   4,5-dimethyl-thiazol-2-yl, 1H-imidazol-4-yl-methyl,            thiazol-2-yl-methyl, 4-methyl-thiazol-5-yl-methyl,            4-methyl-thiazol-2-yl-methyl, 5-methyl-thiazol-2-yl-methyl,            2-methyl-thiazol-4-yl-methyl, oxazol-5-yl-methyl,            1-(2H-pyrazol-3-yl)-ethyl,            (1-methyl-1H-pyrazol-3-yl)-methyl,            1-([1,2,4]oxadiazol-3-yl)-ethyl, 1-(isoxazol-3-yl)-ethyl,            3-methyl-isoxazol-5-yl-methyl,            5-methyl-isoxazol-3-yl-methyl,            1-(1H-[1,2,4]triazol-3-yl)-ethyl,            (1,5-dimethyl-1H-pyrazol-3-yl)-methyl,            (2,5-dimethyl-2H-pyrazol-3-yl)-methyl,            (3-ethyl-([1,2,4]oxadiazol-5-yl)-methyl,            1-(5-methyl-([1,3,4]oxadiazol-2-yl)-ethyl,            1-methyl-1-(1-methyl-1H-pyrazol-4-yl)-ethyl,            1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl, or            1-(4-methyl-thiazol-2-yl)-cyclobutyl; or        -   pyridin-3-yl, pyridin-2-yl-methyl, pyridin-3-yl-methyl,            pyridin-4-yl-methyl, pyrimidin-2-yl-methyl,            pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl,            1-(pyridin-2-yl)-ethyl, 1-(pyridin-3-yl)-ethyl,            2-(pyridin-2-yl)-ethyl, 1-methyl-1-(pyridin-2-yl)-ethyl,            1-(pyrazin-2-yl)-ethyl, 1-(pyrimidin-4-yl)-ethyl,            1-(5-fluoro-pyrimidin-2-yl)-ethyl,            1-(3-fluoro-pyridin-2-yl)-ethyl,            1-(5-fluoro-pyridin-2-yl)-ethyl,            1-(6-methyl-pyridin-2-yl)-ethyl,            2-hydroxy-1-(pyridin-2-yl)-ethyl,            1-(1-oxy-pyridin-2-yl)-ethyl, 1-(pyridin-2-yl)-cyclopropyl,            1-(pyridin-4-yl)-cyclopropyl, 1-(pyrazin-2-yl)-cyclopropyl,            1-(pyridazin-3-yl)-cyclopropyl,            1-(pyrimidin-2-yl)-cyclopropyl,            1-(5-fluoro-pyridin-2-yl)-cyclopropyl,            1-(3,5-difluoro-pyridin-2-yl)-ethyl,            2,2,2-trifluoro-1-(pyridin-2-yl)-ethyl,            1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl; or            (6-methyl-pyridin-2-yl)-methyl, 1-(pyrimidin-2-yl)-ethyl,            1-methyl-1-(pyrimidin-2-yl)-ethyl,            1-(pyrimidin-4-yl)-cyclopropyl,            2-(pyrimidin-2-yl)-cyclobutyl,            2-(pyrimidin-2-yl)-cyclopentyl,            1-(1-oxy-pyrimidin-2-yl)-cyclopropyl,            1-(3-fluoro-pyridin-2-yl)-cyclopropyl,            [1-(pyridin-2-yl)-cyclopropyl]-methyl,            1-(pyridin-2-yl)-cyclobutyl,            1-(1-oxy-pyridin-2-yl)-cyclopropyl,            2-methyl-2-(pyridin-2-yl)-propyl,            2-methyl-2-(3-methyl-pyridin-2-yl)-propyl);    -   and R^(N2) independently represents hydrogen, (C₁₋₄)alkyl        (especially methyl, ethyl, isopropyl) or (C₂₋₃)fluoroalkyl        (especially 2-fluoro-ethyl);    -   or R^(N1) and R^(N2) together with the nitrogen atom to which        they are attached to form a 4- to 6-membered ring selected from        -   azetidinyl, pyrrolidinyl or piperidinyl; each independently            unsubstituted;            -   or mono-substituted with fluoro, methyl, or hydroxy;            -   or di-substituted with fluoro;            -   or mono-substituted with Ar⁴, wherein Ar⁴ represents                phenyl, or 5- or 6-membered heteroaryl (especially                pyridinyl); wherein said phenyl or 5- or 6-membered                heteroaryl independently is (especially) unsubstituted,                or mono-, or di-substituted; wherein the substituents                are independently selected from (C₁₋₄)alkyl,                (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or                (C₁₋₃)fluoroalkoxy; or        -   morpholinyl;        -   (especially such cyclic group R^(N1)R^(N2)N— is            azetidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,            3-fluoro-azetidin-1-yl, 3,3-difluoro-azetidin-1-yl,            3-hydroxy-pyrrolidin-1-yl, 3-phenyl-pyrrolidin-1-yl,            3-(pyridin-2-yl)-pyrrolidin-1-yl);    -   R² represents    -   hydrogen;    -   (C₁₋₆)alkyl (especially ethyl, isopropyl, isobutyl, tert.-butyl,        2,2-dimethylpropyl, 3-methyl-butyl, 3,3-dimethylbutyl);    -   (C₂₋₆)alkyl which is mono-substituted with (C₁₋₃)alkoxy        (especially methoxy), or hydroxy (especially 2-hydroxyethyl,        2-methoxy-ethyl, 2-hydroxy-1-methyl-propyl);    -   (C₃₋₅)alkenyl (especially allyl);    -   cyano-methyl;    -   (C₂₋₃)fluoroalkyl (especially 3-fluoro-propyl);    -   (C₃₋₈)cycloalkyl-(C₀₋₃)alkyl; wherein the (C₃₋₈)cycloalkyl is        unsubstituted, or mono- or di-substituted wherein the        substituents are independently selected from (C₁₋₃)alkyl    -   (especially methyl), fluoro, hydroxy, hydroxy-(C₁₋₃)alkyl        (especially hydroxy-methyl), (C₁₋₃)alkoxy (especially methoxy),        or (C₁₋₃)fluoroalkyl (especially difluoromethyl); (especially        cyclobutyl, 2-methylcyclobutyl, 2,2-dimethylcyclobutyl,        3,3-dimethylcyclobutyl, cyclopentyl, cyclohexyl,        spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl,        bicyclo[2.2.1]hept-2-yl, 2-methylcyclopentyl,        2-(hydroxymethyl)-cyclopentyl, 3,3-dimethylcyclopentyl,        2-ethylcyclopentyl, 3,3-dimethylcyclohexyl, 2-fluoro-cyclohexyl,        4-fluoro-cyclohexyl, 4,4-difluoro-cyclohexyl,        2-hydroxy-cyclohexyl, 2-methoxy-cyclohexyl,        3-methoxy-cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,        cyclopentylmethyl, 1-cyclopropyl-ethyl,        (1-methyl-cyclopropyl)-methyl, (1-methyl-cyclobutyl)-methyl,        2-cyclopropyl-ethyl; or (1-fluoro-cyclopropyl)-methyl,        spiro[2.3]hex-5-yl, bicyclo[3.1.0]hex-3-yl,        3,3-difluorocyclobutyl, (2,2-difluorocyclopropyl)-methyl,        (3,3-difluorocyclobutyl)-methyl,        (1-difluoromethyl-cyclopropyl)-methyl); thietan-3-yl;    -   (C₃₋₈)cycloalkenyl-(C₁₋₃)alkyl (especially        cyclopenten-1-yl-methyl); or    -   Ar⁵—CH₂— wherein Ar⁵ represents phenyl, or 5- or 6-membered        heteroaryl (especially pyrrolyl), wherein the phenyl or 5- or        6-membered heteroaryl independently is unsubstituted, or mono-        or di-substituted wherein the substituents are independently        selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,        (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; [especially such group        Ar⁵—CH₂— is benzyl wherein the phenyl ring of said benzyl is        unsubstituted, or mono- or di-substituted wherein the        substituents are independently selected from (C₁₋₄)alkyl,        (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;        in particular benzyl wherein the phenyl ring of said benzyl is        unsubstituted, or mono-substituted with halogen (especially        benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, 4-fluoro-benzyl)]; and    -   R³ represents hydrogen, or methyl (especially hydrogen).

The compounds of formula (I) contain at least two stereogenic centerswhich are situated in position 3 and 4 of the piperidine moiety. It isunderstood that the two substituents of the piperidine ring: R¹—CO— and—NH—CO-Art-Ar², are in relative trans-configuration (i.e. the relativeconfiguration of said two chiral carbon atoms in position 3 and 4 of thepiperidine ring is (3R*,4R*)). Thus, a compound of formula (I)represents either a compound of formula (I_(R)), or a compound offormula (Is), or any mixture thereof:

The relative configuration of stereoisomers is thus denoted as follows:

for example(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-chloro-phenyl)-ethyl]-amide denominates(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-chloro-phenyl)-ethyl]-amide,(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-chloro-phenyl)-ethyl]-amide,or any mixture of these two enantiomers including the racemate.

In addition, the compounds of formulae (I), (I_(R)), and (I_(S)) maycontain one or more further stereogenic or asymmetric centers, such asone or more additional asymmetric carbon atoms. The compounds offormulae (I), (I_(R)), and (I_(S)) may thus be present as mixtures ofstereoisomers or preferably as pure stereoisomers. Mixtures ofstereoisomers may be separated in a manner known to a person skilled inthe art.

In case a particular compound (or generic structure) is designated as(R)- or (S)-enantiomer/as having an absolute (R)- or (S)-configuration,such designation is to be understood as referring to the respectivecompound (or generic structure) in enriched, especially essentiallypure, enantiomeric form. Likewise, in case a specific asymmetric centerin a compound is designated as being in (R)- or (S)-configuration or asbeing in a certain relative configuration, such designation is to beunderstood as referring to the compound that is in enriched, especiallyessentially pure, form with regard to the respective configuration ofsaid asymmetric center. In analogy, cis- or trans-designations (or(R*,R*) designations) are to be understood as referring to therespective stereoisomer of the respective relative configuration inenriched form, especially in essentially pure form.

The term “enriched”, when used in the context of stereoisomers, is to beunderstood in the context of the present invention to mean that therespective stereoisomer is present in a ratio of at least 70:30,especially of at least 90:10 (i.e., in a purity of at least 70% byweight, especially of at least 90% by weight), with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

The term “essentially pure”, when used in the context of stereoisomers,is to be understood in the context of the present invention to mean thatthe respective stereoisomer is present in a purity of at least 95% byweight, especially of at least 99% by weight, with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

In some instances, the compounds of formula (I) may contain tautomericforms. Such tautomeric forms are encompassed in the scope of the presentinvention. For example, in case the present compounds containheteroaromatic aromatic rings containing unsubstituted ring nitrogenatoms having a free valency such as imidazol-2,4-diyl, or[1,2,4]-triazol-3,5-diyl, such rings may be present in tautomeric forms.For example, the group imidazol-2,4-diyl represents the tautomeric forms1H-imidazol-2,4-diyl and 3H-imidazol-2,4-diyl; and the group[1,2,4]triazol-3,5-diyl represents the tautomeric forms1H-[1,2,4]triazol-3,5-diyl, 2H-[1,2,4]triazol-3,5-diyl and4H-[1,2,4]triazol-3,5-diyl.

The present invention also includes isotopically labelled, especially ²H(deuterium) labelled compounds of formula (I), which compounds areidentical to the compounds of formula (I) except that one or more atomshave each been replaced by an atom having the same atomic number but anatomic mass different from the atomic mass usually found in nature.Isotopically labelled, especially ²H (deuterium) labelled compounds offormula (I) and salts thereof are within the scope of the presentinvention. Substitution of hydrogen with the heavier isotope ²H(deuterium) may lead to greater metabolic stability, resulting e.g. inincreased in-vivo half-life or reduced dosage requirements, or may leadto reduced inhibition of cytochrome P450 enzymes, resulting e.g. in animproved safety profile. In one embodiment of the invention, thecompounds of formula (I) are not isotopically labelled, or they arelabelled only with one or more deuterium atoms. In a sub-embodiment, thecompounds of formula (I) are not isotopically labelled at all.Isotopically labelled compounds of formula (I) may be prepared inanalogy to the methods described hereinafter, but using the appropriateisotopic variation of suitable reagents or starting materials.

Deuterated groups are denominated as follows: for example the group(1,1,2,2,2-d₅-ethyl) denominates the residue

In this patent application, a bond drawn as a dotted line shows thepoint of attachment of the radical drawn. For example, the radical drawnbelow

is an isoxazol-3,5-diyl group.

Where the plural form is used for compounds, salts, pharmaceuticalcompositions, diseases and the like, this is intended to mean also asingle compound, salt, or the like.

Any reference to compounds of formula (I) is to be understood asreferring also to the salts (and especially the pharmaceuticallyacceptable salts) of such compounds, as appropriate and expedient.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the subject compound and exhibitminimal undesired toxicological effects. Such salts include inorganic ororganic acid and/or base addition salts depending on the presence ofbasic and/or acidic groups in the subject compound. For reference seefor example “Handbook of Pharmaceutical Salts. Properties, Selection andUse.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008;and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere(Eds.), RSC Publishing, 2012.

Definitions provided herein are intended to apply uniformly to thecompounds of formula (I), as defined in any one of embodiments 1) to19), and 27), and, mutatis mutandis, throughout the description and theclaims unless an otherwise expressly set out definition provides abroader or narrower definition. It is well understood that a definitionor preferred definition of a term defines and may replace the respectiveterm independently of (and in combination with) any definition orpreferred definition of any or all other terms as defined herein. If notexplicitly defined otherwise in the respective embodiment or claim,groups defined herein are unsubstituted.

The term “halogen” means fluorine, chlorine, bromine, or iodine,preferably fluorine or chlorine, especially fluorine.

The term “alkyl”, used alone or in combination, refers to a saturatedstraight or branched chain hydrocarbon group containing one to six(especially one to four) carbon atoms. The term “(C_(x-y))alkyl” (x andy each being an integer), refers to an alkyl group as defined before,containing x to y carbon atoms. For example a (C₁₋₆)alkyl group containsfrom one to six carbon atoms. Examples of alkyl groups are methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,n-pentyl, 1,1-dimethyl-propyl, 2,2-dimethyl-propyl, 3-methyl-butyl, and1,1,2-trimethyl-propyl. Particular examples of (C₁₋₆)alkyl groups asused for R² are ethyl, isopropyl, 2,2-dimethyl-propyl, 3-methyl-butyland 3,3-dimethyl-butyl. Particular examples of (C₁₋₆)alkyl groups asused for R^(N1) are methyl, ethyl, isopropyl, isobutyl, tert.-butyl and1,1,2-trimethyl-propyl. Particular examples of (C₁₋₄)alkyl groups asused for R^(N2) are methyl, ethyl, and isopropyl, especially methyl.Particular examples of (C₁₋₄)alkyl groups which are substituents of Ar¹,Ar³ or Ar⁴ are methyl and ethyl, especially methyl.

Examples of “(C₁₋₆)alkyl which is mono-substituted with (C₁₋₃)alkoxy, orhydroxy” as used for R² are 2-hydroxy-ethyl, 2-hydroxy-propyl,2-hydroxy-1-methyl-propyl, and 2-methoxy-ethyl.

The term “—(C₁₋₆)alkylene-”, used alone or in combination, refers tobivalently bound alkyl group as defined before containing x to y carbonatoms. Preferably, the points of attachment of any bivalently boundalkyl group are in 1,1-diyl, or in 1,2-diyl arrangement. In case a(C_(0-y))alkylene group is used in combination with another substituent,the term means that either said substituent is directly attached to therest of the molecule (i.e. the (C₀)alkyl group represents a direct bondlinking said substituent to the rest of the molecule), or it is linkedthrough a (C_(1-y))alkylene group to the rest of the molecule. Examplesof —(C₁₋₄)alkylene- are the —(C₁₋₃)alkylene- groups methylene, ethylene,ethan-1,1-diyl, propan-1,2-diyl, and propan-2,2-diyl, as well as the—(C₄)alkylene- group 2-methyl-propan-1,2-diyl. In case a linker group isa —(C₀)alkylene- group, such group refers to a direct bond.

Examples of “—(C₁₋₃)alkylene- which is mono-substituted with hydroxy ortrifluoromethyl” as used for L² are 1-trifluoromethyl-ethan-1,1-diyl,2-hydroxy-ethan-1,2-diyl, and 2-hydroxy-ethan-1,1-diyl.

The term “alkynyl”, used alone or in combination, refers to a straightor branched chain hydrocarbon group containing one to six (especiallyone to four) carbon atoms wherein said hydrocarbon group contains atleast one carbon-carbon triple bond. The term “(C_(x-y))alkynyl” (x andy each being an integer), refers to an alkynyl group as defined before,containing x to y carbon atoms. For example a (C₂₋₆)alkynyl groupcontains from two to six carbon atoms. An example of an alkynyl group is1-methyl-prop-2-ynyl.

The term “alkenyl”, used alone or in combination, refers to a straightor branched chain hydrocarbon group containing one to six (especiallyone to four) carbon atoms wherein said hydrocarbon group contains atleast one carbon-carbon double bond. The term “(C_(x-y))alkenyl” (x andy each being an integer), refers to an alkenyl group as defined before,containing x to y carbon atoms. For example a (C₂₋₆)alkenyl groupcontains from two to six carbon atoms. An example of an alkenyl group isallyl.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O—group wherein the alkyl group is as defined before. The term“(C_(x-y))alkoxy” (x and y each being an integer) refers to an alkoxygroup as defined before containing x to y carbon atoms. For example a(C₁₋₄)alkoxy group means a group of the formula (C₁₋₄)alkyl-O— in whichthe term “(C₁₋₄)alkyl” has the previously given significance. Examplesof alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.-butoxy and tert.-butoxy. A preferred example is methoxy.

The term “fluoroalkyl” refers to an alkyl group as defined beforecontaining one to five carbon atoms in which one or more (especially 1,2, or 3; and possibly all) hydrogen atoms have been replaced withfluorine. The term “(C_(x-y))fluoroalkyl” (x and y each being aninteger) refers to a fluoroalkyl group as defined before containing x toy carbon atoms. For example a (C₁₋₃)fluoroalkyl group contains from oneto three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkyl groupsinclude the (C₁)fluoroalkyl groups difluoromethyl and trifluoromethyl,as well as the (C₂₋₅)fluoroalkyl groups 2-fluoro-ethyl,2,2-difluoro-ethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl,3,3,3-trifluoropropyl, 2-fluoro-1-methyl-ethyl,2-fluoro-1,1-dimethyl-ethyl, 2,2-difluoro-1-methyl-ethyl, and3,3,3-trifluoro-1,1-dimethyl-propyl.

The term “(C_(x-y))fluoroalkylene”, used alone or in combination, refersto bivalently bound fluoroalkyl group as defined before containing x toy carbon atoms. Preferably, the points of attachment of any bivalentlybound fluoroalkyl group are in 1,1-diyl arrangement. An example is2,2,2-trifluoro-ethan-1,1-diyl.

The term “fluoroalkoxy” refers to an alkoxy group as defined beforecontaining one to three carbon atoms in which one or more (and possiblyall) hydrogen atoms have been replaced with fluorine. The term“(C_(x-y))fluoroalkoxy” (x and y each being an integer) refers to afluoroalkoxy group as defined before containing x to y carbon atoms. Forexample a (C₁₋₃)fluoroalkoxy group contains from one to three carbonatoms in which one to seven hydrogen atoms have been replaced withfluorine. Representative examples of fluoroalkoxy groups includetrifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxyand 2,2,2-trifluoroethoxy. A preferred example is trifluoromethoxy.

The term “cyano” refers to a group —CN.

The term “cycloalkyl”, used alone or in combination, refers to asaturated mono- or bicyclic carbocyclic ring containing three to eightcarbon atoms, wherein the term “bicyclic cycloalkyl” includes fused,bridged, and spiro-bicyclic cycloalkyl groups. The term“(C_(x-y))cycloalkyl” (x and y each being an integer), refers to acycloalkyl group as defined before containing x to y carbon atoms. Forexample a (C₃₋₈)cycloalkyl group contains from three to eight carbonatoms. Examples of cycloalkyl groups are the mono-cyclic cycloalkylgroups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl; as well as bicyclic cycloalkyl groups such asspiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl, bicyclo[2.2.1]hept-2-yl,spiro[2.3]hex-5-yl, and bicyclo[3.1.0]hex-3-yl. Preferred arecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “—(C_(x-y))cycloalkylene-”, used alone or in combination,refers to bivalently bound cycloalkyl group as defined before containingx to y carbon atoms. Preferably, the points of attachment of anybivalently bound cycloalkyl group are in 1,1-diyl, or in 1,2-diylarrangement. Examples are cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,cyclobutan-1,1-diyl, and cyclopentan-1,3-diyl; preferred arecyclopropan-1,1-diyl, and cyclobutan-1,1-diyl.

The term “(C_(x-y))cycloalkyl, wherein said (C_(x-y))cycloalkyloptionally contains one ring oxygen atom”, refers to a(C_(x-y))cycloalkyl group containing x to y carbon atoms, especially amono-cyclic (C₃₋₆)cycloalkyl group, as defined before. In addition, onering carbon atom of said (C_(x-y))cycloalkyl may be replaced by anoxygen atom. Such groups are unsubstituted or substituted as explicitlydefined. Examples are especially the (C₃₋₆)cycloalkyl groupscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; as well as oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl. A preferred“(C_(x-y))cycloalkylene, wherein said (C_(x-y))cycloalkylene optionallycontains one ring oxygen atom” is oxetan-3,3-diyl.

The term “(C₃₋₈)cycloalkyl-(C₀₋₃)alkyl” refers to a (C₃₋₈)cycloalkylgroup as defined before (i.e. such group may optionally contain ring aoxygen atom as explicitly defined) which group is linked to the rest ofthe molecule through a (C₀₋₃)alkylene group as defined before. The(C₃₋₈)cycloalkyl group part of (C₃₋₈)cycloalkyl-(C₀₋₃)alkyl isunsubstituted or substituted as explicitly defined. The (C₀₋₃)alkylenegroup part of (C₃₋₈)cycloalkyl-(C₀₋₃)alkyl is unsubstituted, orsubstituted as explicitly defined.

The term “cycloalkenyl”, used alone or in combination, refers to anon-aromatic, unsaturated (i.e. containing at least one ringcarbon-carbon-double bond) mono- or bicyclic carbocyclic ring containingthree to eight carbon atoms, wherein the term “bicyclic cycloalkenyl”includes fused, bridged, and spiro-bicyclic cycloalkenyl groups. Theterm “(C_(x-y))cycloalkenyl” (x and y each being an integer), refers toa cycloalkenyl group as defined before containing x to y carbon atoms.For example a (C₃₋₈)cycloalkenyl group contains from three to eightcarbon atoms. Examples of cycloalkenyl groups are cyclopentenyl,cyclohexenyl, cycloheptenyl and cyclooctenyl; especiallycyclopenten-1-yl.

The term “aryl”, used alone or in combination, means phenyl or naphthyl,preferably phenyl. Likewise, an arylene group is an aryl group asdefined before having two points of attachment to the respective restsof the molecule. The above-mentioned aryl/arylene groups areunsubstituted or substituted as explicitly defined.

For the substituent Ar² representing “phenyl, wherein said phenyl ismono-, di- or tri-substituted, wherein the substituents areindependently selected from fluoro, chloro, methyl, cyano, methoxy, or(C₁)fluoroalkyl” particular groups are those where one or two of saidsubstituents is/are independently selected from fluoro, chloro, andmethyl, and the remaining, if present, is/are fluoro. Especially Ar²represents phenyl which is mono-, di- or tri-substituted, wherein thesubstituents are independently fluoro or chloro; in particular Ar²represents phenyl which is mono-, di- or tri-substituted with fluoro, orphenyl which is mono-, di- or tri-substituted wherein one substituent ischloro and the remaining substituents, if present, are fluoro. Examplesof Ar² are 2-fluoro-phenyl, 4-fluoro-phenyl, 2,4-difluoro-phenyl,2,4,6-trifluoro-phenyl, 4-chloro-2-fluoro-phenyl,2-chloro-4-fluoro-phenyl, 2,4-dichlorophenyl, 2,3,4-trifluoro-phenyl,2,4-dimethylphenyl, 2-methylphenyl, 3,4-dimethylphenyl,2,3-difluoro-phenyl, 3,4-difluoro-phenyl, 4-cyano-phenyl,4-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,2-trifluoromethyl-phenyl, and 2-fluoro-4-methoxy-phenyl. Preferredexamples are 2,4-difluoro-phenyl, 2,4,6-trifluoro-phenyl,2,4-dichlorophenyl, 2,3,4-trifluoro-phenyl, and 2,4-dimethylphenyl(especially 2,4-difluoro-phenyl).

For the substituent Ar³ representing phenyl, the phenyl isunsubstituted, or substituted as explicitly defined. Examples arephenyl, 2-chloro-phenyl, 4-fluoro-phenyl, 2-methyl-phenyl,3-methyl-phenyl, 4-methyl-phenyl, and 2-methoxy-phenyl; as well as3-bromo-phenyl, 3-chloro-phenyl, 4-fluoro-phenyl, 3-fluoro-phenyl,2-fluoro-phenyl, 2-hydroxy-phenyl, 2-methoxy-phenyl, 4-chloro-phenyl,3-methoxy-phenyl, and 2-trifluoromethyl-phenyl.

The term “aryl-(C_(x-y))alkyl” refers to an aryl group as defined beforewhich is linked to the rest of the molecule through a (C_(x-y))alkylenegroup as defined before. The aryl group part of aryl-(C_(x-y))alkyl isunsubstituted or substituted as explicitly defined. The(C_(x-y))alkylene group part of aryl-(C_(x-y))alkyl is unsubstituted, orsubstituted as explicitly defined.

The term “aryl-(C_(x-y))cycloalkyl” refers to an aryl group as definedbefore which is linked to the rest of the molecule through a(C_(x-y))cycloalkylene group as defined before. The aryl group part ofaryl-(C_(x-y))cycloalkyl is unsubstituted or substituted as explicitlydefined. The (C_(x-y))cycloalkylene group part ofaryl-(C_(x-y))cycloalkyl is unsubstituted, or substituted as explicitlydefined.

The term “heteroaryl”, used alone or in combination, means a 5- to10-membered monocyclic or bicyclic aromatic ring containing one to amaximum of four heteroatoms (notably containing one to a maximum ofthree heteroatoms), each independently selected from oxygen, nitrogenand sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl,isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl,thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl,isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, andimidazothiazolyl. Likewise, a heteroarylene group is a heteroaryl groupas defined before having two points of attachment to the respectiverests of the molecule. The above-mentioned heteroaryl/heteroarylenegroups are unsubstituted or substituted as explicitly defined.

For the group Ar¹ representing a 5-membered heteroarylene, the termmeans a 5-membered heteroarylene group as defined above (wherein said5-membered heteroarylene notably contains one to a maximum of threeheteroatoms); which is bound to the rest of the molecule as explicitlydefined. The term “meta arrangement” in the context of a heteroarylenegroup such as Ar¹ means that the respective substituents are attached ina relative 1,3-arrangement. Examples of Ar¹ representing 5-memberedheteroarylene are especially 5-membered heteroarylene groups containingone to a maximum of three heteroatoms, each independently selected fromoxygen, nitrogen and sulfur (especially 5-membered heteroarylenecontaining one to a maximum of three heteroatoms, each independentlyselected from oxygen and nitrogen; or 5-membered heteroarylenecontaining one sulfur ring atom and one to a maximum of two nitrogenring atoms); notably oxazol-diyl, isoxazol-diyl, oxadiazol-diyl, ortriazol-diyl; or thiadiazol-diyl, or isothiazol-diyl; in particularoxazol-2,5-diyl, oxazol-2,4-diyl, isoxazol-3,5-diyl,[1,3,4]oxadiazol-2,5-diyl, [1,2,4]oxadiazol-3,5-diyl, or1H-[1,2,3]triazol-1,4-diyl; or [1,3,4]thiadiazol-2,5-diyl, orisothiazol-3,5-diyl. Preferred examples of Ar¹ representing a 5-memberedheteroarylene group are oxazol-2,5-diyl wherein the substituent Ar² isattached to the carbon atom in position 5; oxazol-2,4-diyl wherein thesubstituent Ar² is attached to the carbon atom in position 4;isoxazol-3,5-diyl wherein the substituent Ar² is attached to the carbonatom in position 5; isoxazol-3,5-diyl wherein the substituent Ar² isattached to the carbon atom in position 3; [1,3,4]oxadiazol-2,5-diyl;[1,2,4]oxadiazol-3,5-diyl wherein the substituent Ar² is attached to thecarbon atom in position 5; 1H-[1,2,3]triazol-1,4-diyl wherein thesubstituent Ar² is attached to the nitrogen atom in position 1;[1,3,4]thiadiazol-2,5-diyl; and isothiazol-3,5-diyl wherein thesubstituent Ar² is attached to the carbon atom in position 5.

For the substituent Ar² representing “6-membered heteroaryl, whereinsaid 6-membered heteroaryl independently is mono-, di- ortri-substituted, wherein two of said the substituents are independentlyselected from fluoro, chloro, methyl, cyano, methoxy, or(C₁)fluoroalkyl; and the remaining substituent, if present, is fluoro”,examples are especially pyridinyl groups which are mono-, ordi-substituted with fluoro. An example is 5-fluoro-pyridin-2-yl.

For the substituent Ar³ representing 5- or 6-membered heteroaryl, theterm means 5- or 6-membered heteroaryl groups as defined above. Examplesof Ar³ representing 6-membered heteroaryl are pyrimidinyl, pyridinyl,pyridazinyl, and pyrazinyl. For avoidance of doubt, the term 6-memberedheteroaryl as used for the substituent Ar³ in addition comprises thegroups 1-oxy-pyridinyl, and 1-oxy-pyrimidinyl. Particular examples arepyrazin-2-yl, pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; as well as the N-oxides1-oxy-pyrimidin-2-yl and 1-oxy-pyridin-2-yl. The 6-membered heteroarylgroups as used for the substituent Ar³ are preferably unsubstituted; orsaid groups are substituted as explicitly defined (especially mono- ordisubstituted wherein the substituents are independently selected fromfluoro or methyl). Examples of Ar³ representing 5-membered heteroarylare oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,and triazolyl; in particular oxazol-5-yl, isoxazol-3-yl, isoxazol-5-yl,thiazol-2-yl, thiazol-5-yl, thiazol-4-yl, imidazol-4-yl,2H-pyrazol-3-yl, 1H-pyrazol-3-yl, 2H-pyrazol-3-yl, 1H-pyrazol-4-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, and1H-[1,2,4]triazol-3-yl. The 5-membered heteroaryl groups as used for thesubstituent Ar³ are unsubstituted; or said groups are substituted asexplicitly defined (especially mono- or disubstituted wherein thesubstituents are independently selected from methyl or ethyl).

An example of Ar⁴ representing 5- or 6-membered heteroaryl is pyridinyl.

An example of Ar⁵—CH₂— wherein Ar⁵ represents 5- or 6-memberedheteroaryl is (1-methyl-pyrrol-3-yl)-methyl.

The term “heteroaryl-(C_(x-y))alkyl” refers to a heteroaryl group asdefined before which is linked to the rest of the molecule through a(C_(x-y))alkylene group as defined before. The heteroaryl group part ofheteroaryl-(C_(x-y))alkyl is unsubstituted or substituted as explicitlydefined. The (C_(x-y))alkylene group part of heteroaryl-(C_(x-y))alkylis unsubstituted, or substituted as explicitly defined.

The term “heteroaryl-(C_(x-y))cycloalkyl” refers to a heteroaryl groupas defined before which is linked to the rest of the molecule through a(C_(x-y))cycloalkylene group as defined before. The heteroaryl grouppart of heteroaryl-(C_(x-y))cycloalkyl is unsubstituted or substitutedas explicitly defined. The (C_(x-y))cycloalkylene group part ofheteroaryl-(C_(x-y))cycloalkyl is unsubstituted, or substituted asexplicitly defined.

Further embodiments of the invention are presented hereinafter:

2) A further embodiment relates to the compounds of formula (I)according to embodiment 1) which are also compounds of Formula (I_(R)),wherein the two substituents of the piperidine ring: R¹—CO— and—NH—CO—Ar²—Ar², are in relative trans-configuration, wherein theabsolute configuration of the two chiral carbon atoms in position 3 and4 of the piperidine ring is (3R,4R):

3) A further embodiment relates to the compounds of formula (I)according to embodiment 1) which are also compounds of Formula (Is),wherein the two substituents of the piperidine ring: R¹—CO— and—NH—CO—Ar¹—Ar², are in relative trans-configuration, wherein theabsolute configuration of the two chiral carbon atoms in position 3 and4 of the piperidine ring is (3S,4S):

4) A further embodiment relates to the compounds according to any one ofembodiments 1) to 3), wherein R³ represents hydrogen.5) A further embodiment relates to the compounds of formula (I)according to any one of embodiments 1) to 4), wherein Ar¹ represents a5-membered heteroarylene group (especially a 5-membered heteroarylenecontaining one to a maximum of three heteroatoms, each independentlyselected from oxygen and nitrogen (notably oxazol-diyl, isoxazol-diyl,oxadiazol-diyl, or triazol-diyl); or a 5-membered heteroarylenecontaining one sulfur ring atom and one or two nitrogen ring atoms(notably isothiazolyl, or thiadiazol-diyl)), wherein the —NH—CO—groupand Ar² are attached in meta arrangement to ring atoms of Ar¹; whereinsaid 5-membered heteroarylene is unsubstituted.6) A further embodiment relates to the compounds of formula (I)according to any one of embodiments 1) to 4), wherein Ar¹ represents a5-membered heteroarylene group selected from oxazol-diyl, isoxazol-diyl,oxadiazol-diyl, or triazol-diyl, wherein the —NH—CO— group and Ar² areattached in meta arrangement to ring atoms of Ar¹; wherein said5-membered heteroarylene is unsubstituted, or mono-substituted withR^(Ar1); wherein R^(Ar1) represents methyl, methoxy, fluorine, chlorine,trifluoromethyl, or trifluoromethoxy (especially said 5-memberedheteroarylene is unsubstituted).7) A further embodiment relates to the compounds of formula (I)according to any one of embodiments 1) to 4), wherein Ar¹ represents a5-membered heteroarylene group selected from oxazol-2,5-diyl,oxazol-2,4-diyl, isoxazol-3,5-diyl, [1,3,4]oxadiazol-2,5-diyl,[1,2,4]oxadiazol-3,5-diyl, 1H-[1,2,3]triazol-1,4-diyl,[1,3,4]thiadiazol-2,5-diyl, or isothiazol-3,5-diyl; wherein said5-membered heteroarylene is unsubstituted [especially Ar¹ represents a5-membered heteroarylene group selected from oxazol-2,5-diyl wherein thesubstituent Ar² is attached to the carbon atom in position 5;oxazol-2,4-diyl wherein the substituent Ar² is attached to the carbonatom in position 4; isoxazol-3,5-diyl wherein the substituent Ar² isattached to the carbon atom in position 5; isoxazol-3,5-diyl wherein thesubstituent Ar² is attached to the carbon atom in position 3;[1,3,4]oxadiazol-2,5-diyl; [1,2,4]oxadiazol-3,5-diyl wherein thesubstituent Ar² is attached to the carbon atom in position 5;1H-[1,2,3]triazol-1,4-diyl wherein the substituent Ar² is attached tothe nitrogen atom in position 1; [1,3,4]thiadiazol-2,5-diyl; orisothiazol-3,5-diyl wherein the substituent Ar² is attached to thecarbon atom in position 5].8) A further embodiment relates to the compounds of formula (I)according to any one of embodiments 1) to 4), wherein Ar¹ represents(preferably) unsubstituted isoxazol-3,5-diyl, wherein the substituentAr² is attached to the carbon atom in position 5; or Ar¹ represents[1,3,4]thiadiazol-2,5-diyl.9) A further embodiment relates to the compounds of formula (I)according to any one of embodiments 1) to 8), wherein Ar² representsphenyl which is mono-, di- or tri-substituted; wherein one or two ofsaid substituents is/are independently selected from fluoro, chloro, andmethyl, and the remaining, if present, is/are fluoro (especially2,4-difluoro-phenyl).

In a sub-embodiment, Ar² represents phenyl which is mono-, di- ortri-substituted, wherein the substituents are independently fluoro orchloro; in particular Ar² represents phenyl which is mono-, di- ortri-substituted with fluoro (especially 2,4-difluoro-phenyl).

10) A further embodiment relates to the compounds of formula (I)according to any one of embodiments 1) to 8), wherein Ar² represents2-fluoro-phenyl, 4-fluoro-phenyl, 2,4-difluoro-phenyl,2,4,6-trifluoro-phenyl, 4-chloro-2-fluoro-phenyl,2-chloro-4-fluoro-phenyl, 2,4-dichlorophenyl, 2,3,4-trifluoro-phenyl,2,4-dimethylphenyl, 2-methylphenyl, 3,4-dimethylphenyl,2,3-difluoro-phenyl, 3,4-difluoro-phenyl, 4-cyano-phenyl,4-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,2-trifluoromethyl-phenyl, or 2-fluoro-4-methoxy-phenyl. In asub-embodment, Ar² represents 2-fluoro-phenyl, 4-fluoro-phenyl,2,4-difluoro-phenyl, 2,4,6-trifluoro-phenyl, 4-chloro-2-fluoro-phenyl,or 2-chloro-4-fluoro-phenyl (especially Ar² represents2,4-difluoro-phenyl).11) A further embodiment relates to the compounds of formula (I)according to any one of embodiments 1) to 10), wherein R¹ representsR^(N1)R^(N2)N—, wherein

-   -   R^(N1) represents        -   (C₁₋₆)alkyl (especially methyl, ethyl, isopropyl, isobutyl,            tert.-butyl, 1,2,2-trimethyl-propyl);        -   (C₁₋₆)alkyl which is mono-substituted with            -   hydroxy;            -   (C₁₋₃)alkoxy (especially methoxy, ethoxy);            -   2-hydroxy-ethoxy;            -   —CO—NH₂;            -   —SO₂—(C₁₋₃)alkyl (especially methanesulfonyl);            -   cyano;            -   (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy);            -   —NR^(N3)R^(N4), wherein R^(N3) and R^(N4) independently                represent hydrogen or                -   (C₁₋₄)alkyl (especially —NR^(N3)R^(N4) represents                    dimethylamino);        -   (especially such group R^(N1) being mono-substituted            (C₁₋₆)alkyl is 2-hydroxy-ethyl, 2-hydroxy-1-methyl-ethyl,            2-hydroxy-1,1-dimethyl-ethyl, 2-methoxy-ethyl,            3-methoxy-propyl, 2-ethoxy-ethyl, 2-ethoxy-1-methyl-ethyl,            2-methoxy-1,1-dimethyl-ethyl, 3-methoxy-1,1-dimethyl-propyl,            2-(2-hydroxy-ethoxy)-ethyl, carbamoyl-methyl,            2-methanesulfonyl-1,1-dimethyl-ethyl,            1-cyano-1-methyl-ethyl, 2-dimethylamino-ethyl,            2-trifluoromethoxy-ethyl);        -   (C₂₋₆)alkynyl (especially 1-methyl-prop-2-ynyl);        -   (C₂₋₅)fluoroalkyl (especially 2-fluoro-ethyl,            2,2-difluoro-ethyl, 2-fluoro-1-methyl-ethyl,            2-fluoro-1,1-dimethyl-ethyl, 2,2-difluoro-1-methyl-ethyl,            3,3,3-trifluoro-1,1-dimethyl-propyl);        -   2-(2-oxo-pyrrolidin-1-yl)-ethyl;        -   a group -L¹-Cy¹; wherein            -   L¹ represents a direct bond, —(C₁₋₃)alkylene-, or                —(C₃₋₅)cycloalkylene-; and            -   Cy¹ represents (C₃₋₆)cycloalkyl, wherein said                (C₃₋₆)cycloalkyl optionally contains one ring oxygen                atom; wherein said (C₃₋₆)cycloalkyl independently is                unsubstituted; or mono-substituted with fluoro, methyl,                hydroxy, —CO—(C₁₋₄)alkoxy, or cyano; or di-substituted                with fluoro, or tri-substituted with methyl and two                fluoro;        -   (especially such group -L¹-Cy¹ is cyclopropyl, cyclopentyl,            1-methyl-cyclopropyl, 1-methyl-cyclobutyl,            1-cyclopropyl-cyclopropan-1-yl, 1-cyclobutyl-ethyl,            3-methyl-tetrahydrofuran-3-yl, tetrahydrofuran-3-yl-methyl,            tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2-yl-ethyl,            oxetan-3-yl-methyl, 3,3-difluoro-1-methyl-cyclobutyl,            1-(ethoxycarbonyl)-cyclopropyl, or 1-cyano-cyclobutyl);        -   a group -L²-Ar³, wherein            -   L² represents a —(C₁₋₄)alkylene-; —(C₃₋₅)cycloalkylene-                wherein said (C₃₋₅)cycloalkylene optionally contains one                ring oxygen atom; *—(C₃₋₅)cycloalkylene-(C₁₋₂)alkylene-                wherein said (C₃₋₅)cycloalkylene optionally contains one                ring oxygen atom, wherein the asterisk indicates the                bond to which Ar³ is attached;                *—(C₁₋₂)alkylene-(C₃₋₅)cycloalkylene- wherein said                (C₃₋₅)cycloalkylene optionally contains one ring oxygen                atom, wherein the asterisk indicates the bond to which                Ar³ is attached; or —(C₁₋₃)alkylene- which is                mono-substituted with hydroxy or trifluoromethyl; and            -   Ar³ represents phenyl, or 5-membered heteroaryl                containing one oxygen atom and one or two nitrogen                atoms, or 6-membered heteroaryl containing one or two                nitrogen atoms; wherein said phenyl or 5- or 6-membered                heteroaryl independently is unsubstituted, or mono-, or                di-substituted; wherein the substituents are                independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,                halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;                wherein, in case Ar³ represents 6-membered heteroaryl                which is pyridyl or pyrimidinyl, such pyridyl or                pyrimidinyl may additionally be present in form of the                respective N-oxide;        -   (especially such group -L²-Ar³ is benzyl, 1-phenyl-ethyl,            2-phenyl-ethyl, 2-(2-chloro-phenyl)-ethyl,            2-(4-fluoro-phenyl)-ethyl, 2-(2-methyl-phenyl)-ethyl,            2-(3-methyl-phenyl)-ethyl, 2-(4-methyl-phenyl)-ethyl,            2-(2-methoxy-phenyl)-ethyl, 2-phenyl-propyl,            2-hydroxy-1-phenyl-ethyl, 2-hydroxy-2-phenyl-ethyl,            2-phenyl-cyclopropyl; or 1-(3-bromo-phenyl)-ethyl,            1-phenyl-cyclopropyl, 1-phenyl-cyclobutyl,            2-phenyl-cyclobutyl, 1-(3-chloro-phenyl)-cyclopropyl,            1-(4-fluoro-phenyl)-cyclopropyl,            1-(3-fluoro-phenyl)-cyclopropyl,            1-(2-fluoro-phenyl)-cyclopropyl,            1-(2-methyl-phenyl)-cyclopropyl,            1-(2-hydroxy-phenyl)-cyclopropyl,            1-(2-methoxy-phenyl)-ethyl,            2-methyl-2-(2-chloro-phenyl)-propyl,            1-(4-chloro-phenyl)-cyclopropyl-methyl,            3-(3-chloro-phenyl)-oxetan-3-yl,            3-(4-fluoro-phenyl)-oxetan-3-yl,            3-(phenyl)-oxetan-3-yl-methyl, 3-(benzyl)-oxetan-3-yl,            1-(2-methoxy-phenyl)-cyclopropyl,            1-(3-methoxy-phenyl)-cyclopropyl,            1-(2-trifluoromethyl-phenyl)-cyclopropyl; or        -   oxazol-5-yl-methyl, 1-([1,2,4]oxadiazol-3-yl)-ethyl,            1-(isoxazol-3-yl)-ethyl, 3-methyl-isoxazol-5-yl-methyl,            5-methyl-isoxazol-3-yl-methyl,            (3-ethyl-([1,2,4]oxadiazol-5-yl)-methyl,            1-(5-methyl-([1,3,4]oxadiazol-2-yl)-ethyl,            1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl;        -   pyridin-2-yl-methyl, pyridin-3-yl-methyl,            pyridin-4-yl-methyl, pyrimidin-2-yl-methyl,            pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl,            1-(pyridin-2-yl)-ethyl, 1-(pyridin-3-yl)-ethyl,            2-(pyridin-2-yl)-ethyl, 1-methyl-1-(pyridin-2-yl)-ethyl,            1-(pyrazin-2-yl)-ethyl, 1-(pyrimidin-4-yl)-ethyl,            1-(5-fluoro-pyrimidin-2-yl)-ethyl,            1-(3-fluoro-pyridin-2-yl)-ethyl,            1-(5-fluoro-pyridin-2-yl)-ethyl,            1-(6-methyl-pyridin-2-yl)-ethyl,            2-hydroxy-1-(pyridin-2-yl)-ethyl,            1-(1-oxy-pyridin-2-yl)-ethyl, 1-(pyridin-2-yl)-cyclopropyl,            1-(pyridin-4-yl)-cyclopropyl, 1-(pyrazin-2-yl)-cyclopropyl,            1-(pyridazin-3-yl)-cyclopropyl,            1-(pyrimidin-2-yl)-cyclopropyl,            1-(5-fluoro-pyridin-2-yl)-cyclopropyl,            1-(3,5-difluoro-pyridin-2-yl)-ethyl,            2,2,2-trifluoro-1-(pyridin-2-yl)-ethyl,            1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl; or            (6-methyl-pyridin-2-yl)-methyl, 1-(pyrimidin-2-yl)-ethyl,            1-methyl-1-(pyrimidin-2-yl)-ethyl,            1-(pyrimidin-4-yl)-cyclopropyl,            2-(pyrimidin-2-yl)-cyclobutyl,            2-(pyrimidin-2-yl)-cyclopentyl,            1-(1-oxy-pyrimidin-2-yl)-cyclopropyl,            1-(3-fluoro-pyridin-2-yl)-cyclopropyl,            [1-(pyridin-2-yl)-cyclopropyl]-methyl,            1-(pyridin-2-yl)-cyclobutyl,            1-(1-oxy-pyridin-2-yl)-cyclopropyl,            2-methyl-2-(pyridin-2-yl)-propyl,            2-methyl-2-(3-methyl-pyridin-2-yl)-propyl);    -   and R^(N2) independently represents hydrogen, or (C₁₋₄)alkyl        (especially methyl, ethyl, isopropyl).        12) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 10), wherein R¹        represents R^(N1)R^(N2)N—, wherein    -   R^(N1) represents        -   (C₃₋₆)cycloalkyl, wherein said (C₃₋₆)cycloalkyl optionally            contains one ring oxygen atom; wherein said (C₃₋₆)cycloalkyl            independently is unsubstituted, or mono-substituted with            fluoro, methyl, or hydroxy, or di-substituted with fluoro,            or tri-substituted with methyl and two fluoro (especially            cyclopropyl, cyclopentyl, 1-methyl-cyclopropyl,            1-methyl-cyclobutyl, 3-methyl-tetrahydrofuran-3-yl,            3,3-difluoro-1-methyl-cyclobutyl);        -   (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene-, wherein said            (C₃₋₆)cycloalkyl optionally contains one ring oxygen atom            (especially 1-cyclobutyl-ethyl, tetrahydrofuran-3-yl-methyl,            tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2-yl-ethyl,            oxetan-3-yl-methyl);        -   (C₃₋₆)cycloalkyl-(C₃₋₅)cycloalkylene- (especially            1-cyclopropyl-cyclopropan-1-yl);        -   phenyl-(C₁₋₄)alkylene- wherein said phenyl is unsubstituted,            or mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;            (especially such group is benzyl, 1-phenyl-ethyl,            2-phenyl-ethyl, 2-(2-chloro-phenyl)-ethyl,            2-(4-fluoro-phenyl)-ethyl, 2-(2-methyl-phenyl)-ethyl,            2-(3-methyl-phenyl)-ethyl, 2-(4-methyl-phenyl)-ethyl,            2-(2-methoxy-phenyl)-ethyl, 2-phenyl-propyl; or            1-(3-bromo-phenyl)-ethyl, 1-(2-methoxy-phenyl)-ethyl,            2-methyl-2-(2-chloro-phenyl)-propyl);        -   phenyl-(C₁₋₃)alkylene- wherein said —(C₁₋₃)alkylene- is            mono-substituted with hydroxy (especially            2-hydroxy-2-phenyl-ethyl, 2-hydroxy-1-phenyl-ethyl);        -   phenyl-(C₃₋₅)cycloalkylene- wherein said (C₃₋₅)cycloalkylene            optionally contains one ring oxygen atom, and wherein said            phenyl is unsubstituted, or mono-, or di-substituted;            wherein the substituents are independently selected from            (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, hydroxy,            (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; (especially            2-phenyl-cyclopropyl, 1-phenyl-cyclopropyl,            1-phenyl-cyclobutyl, 2-phenyl-cyclobutyl,            1-(3-chloro-phenyl)-cyclopropyl,            1-(4-fluoro-phenyl)-cyclopropyl,            1-(3-fluoro-phenyl)-cyclopropyl,            1-(2-fluoro-phenyl)-cyclopropyl,            1-(2-methyl-phenyl)-cyclopropyl,            1-(2-hydroxy-phenyl)-cyclopropyl,            3-(3-chloro-phenyl)-oxetan-3-yl,            3-(4-fluoro-phenyl)-oxetan-3-yl,            1-(2-methoxy-phenyl)-cyclopropyl,            1-(3-methoxy-phenyl)-cyclopropyl,            1-(2-trifluoromethyl-phenyl)-cyclopropyl);        -   phenyl-(C₃₋₅)cycloalkylene-(C₁₋₂)alkylene- wherein said            (C₃₋₅)cycloalkylene optionally contains one ring oxygen            atom, and wherein said phenyl is unsubstituted, or            mono-substituted with halogen (especially            1-(4-chloro-phenyl)-cyclopropyl-methyl,            3-(phenyl)-oxetan-3-yl-methyl);        -   phenyl-(C₁₋₂)alkylene-(C₃₋₅)cycloalkylene- wherein said            (C₃₋₅)cycloalkylene optionally contains one ring oxygen atom            (especially 3-(benzyl)-oxetan-3-yl);        -   5-membered heteroaryl-(C₁₋₃)alkylene-, wherein said            5-membered heteroaryl contains one oxygen atom and one or            two nitrogen atoms; and wherein said 5-membered heteroaryl            is unsubstituted, or mono-, or di-substituted; wherein the            substituents are independently selected from (C₁₋₄)alkyl,            (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or            (C₁₋₃)fluoroalkoxy; (especially oxazol-5-yl-methyl,            1-([1,2,4]oxadiazol-3-yl)-ethyl, 1-(isoxazol-3-yl)-ethyl,            3-methyl-isoxazol-5-yl-methyl,            5-methyl-isoxazol-3-yl-methyl,            (3-ethyl-([1,2,4]oxadiazol-5-yl)-methyl,            1-(5-methyl-([1,3,4]oxadiazol-2-yl)-ethyl,            1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl);        -   6-membered heteroaryl-(C₁₋₄)alkylene-, wherein said            6-membered heteroaryl contains one or two nitrogen atoms;            and wherein said 6-membered heteroaryl is unsubstituted, or            mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein,            in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl            or pyrimidinyl may additionally be present in form of the            respective N-oxide; (especially pyridin-2-yl-methyl,            pyridin-3-yl-methyl, pyridin-4-yl-methyl,            pyrimidin-2-yl-methyl, pyrimidin-4-yl-methyl,            pyrazin-2-yl-methyl, 1-(pyridin-2-yl)-ethyl,            1-(pyridin-3-yl)-ethyl, 2-(pyridin-2-yl)-ethyl,            1-methyl-1-(pyridin-2-yl)-ethyl, 1-(pyrazin-2-yl)-ethyl,            1-(pyrimidin-4-yl)-ethyl, 1-(5-fluoro-pyrimidin-2-yl)-ethyl,            1-(3-fluoro-pyridin-2-yl)-ethyl,            1-(5-fluoro-pyridin-2-yl)-ethyl,            1-(6-methyl-pyridin-2-yl)-ethyl,            1-(3,5-difluoro-pyridin-2-yl)-ethyl,            (6-methyl-pyridin-2-yl)-methyl, 1-(pyrimidin-2-yl)-ethyl,            1-methyl-1-(pyrimidin-2-yl)-ethyl,            2-methyl-2-(pyridin-2-yl)-propyl,            2-methyl-2-(3-methyl-pyridin-2-yl)-propyl);        -   6-membered heteroaryl-(C₁₋₃)alkylene-, wherein said            —(C₁₋₃)alkylene- is mono-substituted with hydroxy or            trifluoromethyl; wherein said 6-membered heteroaryl contains            one or two nitrogen atoms; (especially            2-hydroxy-1-(pyridin-2-yl)-ethyl,            2,2,2-trifluoro-1-(pyridin-2-yl)-ethyl);        -   6-membered heteroaryl-(C₃₋₅)cycloalkylene-, wherein said            6-membered heteroaryl contains one or two nitrogen atoms;            and wherein said 6-membered heteroaryl is unsubstituted, or            mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein,            in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl            or pyrimidinyl may additionally be present in form of the            respective N-oxide (especially 1-(pyridin-2-yl)-cyclopropyl,            1-(pyridin-4-yl)-cyclopropyl, 1-(pyrazin-2-yl)-cyclopropyl,            1-(pyridazin-3-yl)-cyclopropyl,            1-(pyrimidin-2-yl)-cyclopropyl,            1-(5-fluoro-pyridin-2-yl)-cyclopropyl,            1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl,            1-(pyrimidin-4-yl)-cyclopropyl,            2-(pyrimidin-2-yl)-cyclobutyl,            2-(pyrimidin-2-yl)-cyclopentyl,            1-(1-oxy-pyrimidin-2-yl)-cyclopropyl,            1-(3-fluoro-pyridin-2-yl)-cyclopropyl,            1-(pyridin-2-yl)-cyclobutyl,            1-(1-oxy-pyridin-2-yl)-cyclopropyl);        -   6-membered heteroaryl-(C₃₋₅)cycloalkylene-(C₁₋₂)alkylene-            wherein said 6-membered heteroaryl contains one or two            nitrogen atoms; and wherein said 6-membered heteroaryl is            unsubstituted; (especially            [1-(pyridin-2-yl)-cyclopropyl]-methyl);    -   and R^(N2) independently represents hydrogen (preferred), or        (C₁₋₄)alkyl (especially methyl, ethyl, isopropyl);    -   or R^(N1) represents (C₁₋₃)alkyl (especially methyl, ethyl); and        R^(N2) represents hydrogen, or methyl.        13) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 10), wherein R¹        represents R^(N1)R^(N2)N—, wherein    -   R^(N1) represents        -   (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene-, wherein said            (C₃₋₆)cycloalkyl optionally contains one ring oxygen atom            (especially 1-cyclobutyl-ethyl, tetrahydrofuran-3-yl-methyl,            tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2-yl-ethyl,            oxetan-3-yl-methyl);        -   phenyl-(C₁₋₄)alkylene- wherein said phenyl is unsubstituted,            or mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;            (especially such group is benzyl, 1-phenyl-ethyl,            2-phenyl-ethyl, 2-(2-chloro-phenyl)-ethyl,            2-(4-fluoro-phenyl)-ethyl, 2-(2-methyl-phenyl)-ethyl,            2-(3-methyl-phenyl)-ethyl, 2-(4-methyl-phenyl)-ethyl,            2-(2-methoxy-phenyl)-ethyl, 2-phenyl-propyl; or            1-(3-bromo-phenyl)-ethyl, 1-(2-methoxy-phenyl)-ethyl,            2-methyl-2-(2-chloro-phenyl)-propyl);        -   phenyl-(C₃₋₅)cycloalkylene- wherein said (C₃₋₅)cycloalkylene            optionally contains one ring oxygen atom, and wherein said            phenyl is unsubstituted, or mono-, or di-substituted;            wherein the substituents are independently selected from            (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, hydroxy,            (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; (especially            2-phenyl-cyclopropyl, 1-phenyl-cyclopropyl,            1-phenyl-cyclobutyl, 2-phenyl-cyclobutyl,            1-(3-chloro-phenyl)-cyclopropyl,            1-(4-fluoro-phenyl)-cyclopropyl,            1-(3-fluoro-phenyl)-cyclopropyl,            1-(2-fluoro-phenyl)-cyclopropyl,            1-(2-methyl-phenyl)-cyclopropyl,            1-(2-hydroxy-phenyl)-cyclopropyl,            3-(3-chloro-phenyl)-oxetan-3-yl,            3-(4-fluoro-phenyl)-oxetan-3-yl,            1-(2-methoxy-phenyl)-cyclopropyl,            1-(3-methoxy-phenyl)-cyclopropyl,            1-(2-trifluoromethyl-phenyl)-cyclopropyl);        -   6-membered heteroaryl-(C₁₋₄)alkylene-, wherein said            6-membered heteroaryl contains one or two nitrogen atoms;            and wherein said 6-membered heteroaryl is unsubstituted, or            mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein,            in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl            or pyrimidinyl may additionally be present in form of the            respective N-oxide; (especially pyridin-2-yl-methyl,            pyridin-3-yl-methyl, pyridin-4-yl-methyl,            pyrimidin-2-yl-methyl, pyrimidin-4-yl-methyl,            pyrazin-2-yl-methyl, 1-(pyridin-2-yl)-ethyl,            1-(pyridin-3-yl)-ethyl, 2-(pyridin-2-yl)-ethyl,            1-methyl-1-(pyridin-2-yl)-ethyl, 1-(pyrazin-2-yl)-ethyl,            1-(pyrimidin-4-yl)-ethyl, 1-(5-fluoro-pyrimidin-2-yl)-ethyl,            1-(3-fluoro-pyridin-2-yl)-ethyl,            1-(5-fluoro-pyridin-2-yl)-ethyl,            1-(6-methyl-pyridin-2-yl)-ethyl,            1-(3,5-difluoro-pyridin-2-yl)-ethyl,            (6-methyl-pyridin-2-yl)-methyl, 1-(pyrimidin-2-yl)-ethyl,            1-methyl-1-(pyrimidin-2-yl)-ethyl,            2-methyl-2-(pyridin-2-yl)-propyl,            2-methyl-2-(3-methyl-pyridin-2-yl)-propyl);        -   6-membered heteroaryl-(C₃₋₅)cycloalkylene-, wherein said            6-membered heteroaryl contains one or two nitrogen atoms;            and wherein said 6-membered heteroaryl is unsubstituted, or            mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein,            in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl            or pyrimidinyl may additionally be present in form of the            respective N-oxide (especially 1-(pyridin-2-yl)-cyclopropyl,            1-(pyridin-4-yl)-cyclopropyl, 1-(pyrazin-2-yl)-cyclopropyl,            1-(pyridazin-3-yl)-cyclopropyl,            1-(pyrimidin-2-yl)-cyclopropyl,            1-(5-fluoro-pyridin-2-yl)-cyclopropyl,            1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl,            1-(pyrimidin-4-yl)-cyclopropyl,            2-(pyrimidin-2-yl)-cyclobutyl,            2-(pyrimidin-2-yl)-cyclopentyl,            1-(1-oxy-pyrimidin-2-yl)-cyclopropyl,            1-(3-fluoro-pyridin-2-yl)-cyclopropyl,            1-(pyridin-2-yl)-cyclobutyl,            1-(1-oxy-pyridin-2-yl)-cyclopropyl);    -   and R^(N2) independently represents hydrogen, or (C₁₋₄)alkyl        (especially methyl, ethyl, isopropyl).        14) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 10), wherein R¹        represents R^(N1)R^(N2)N—, wherein    -   R^(N1) represents        -   6-membered heteroaryl-(C₁₋₄)alkylene-, wherein said            6-membered heteroaryl contains one or two nitrogen atoms;            and wherein said 6-membered heteroaryl is unsubstituted, or            mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein,            in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl            or pyrimidinyl may additionally be present in form of the            respective N-oxide; (especially pyridin-2-yl-methyl,            pyridin-3-yl-methyl, pyridin-4-yl-methyl,            pyrimidin-2-yl-methyl, pyrimidin-4-yl-methyl,            pyrazin-2-yl-methyl, 1-(pyridin-2-yl)-ethyl,            1-(pyridin-3-yl)-ethyl, 2-(pyridin-2-yl)-ethyl,            1-methyl-1-(pyridin-2-yl)-ethyl, 1-(pyrazin-2-yl)-ethyl,            1-(pyrimidin-4-yl)-ethyl, 1-(5-fluoro-pyrimidin-2-yl)-ethyl,            1-(3-fluoro-pyridin-2-yl)-ethyl,            1-(5-fluoro-pyridin-2-yl)-ethyl,            1-(6-methyl-pyridin-2-yl)-ethyl,            1-(3,5-difluoro-pyridin-2-yl)-ethyl,            (6-methyl-pyridin-2-yl)-methyl, 1-(pyrimidin-2-yl)-ethyl,            1-methyl-1-(pyrimidin-2-yl)-ethyl,            2-methyl-2-(pyridin-2-yl)-propyl,            2-methyl-2-(3-methyl-pyridin-2-yl)-propyl);        -   6-membered heteroaryl-(C₃₋₅)cycloalkylene-, wherein said            6-membered heteroaryl contains one or two nitrogen atoms;            and wherein said 6-membered heteroaryl is unsubstituted, or            mono-, or di-substituted; wherein the substituents are            independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,            halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein,            in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl            or pyrimidinyl may additionally be present in form of the            respective N-oxide (especially 1-(pyridin-2-yl)-cyclopropyl,            1-(pyridin-4-yl)-cyclopropyl, 1-(pyrazin-2-yl)-cyclopropyl,            1-(pyridazin-3-yl)-cyclopropyl,            1-(pyrimidin-2-yl)-cyclopropyl,            1-(5-fluoro-pyridin-2-yl)-cyclopropyl,            1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl,            1-(pyrimidin-4-yl)-cyclopropyl,            2-(pyrimidin-2-yl)-cyclobutyl,            2-(pyrimidin-2-yl)-cyclopentyl,            1-(1-oxy-pyrimidin-2-yl)-cyclopropyl,            1-(3-fluoro-pyridin-2-yl)-cyclopropyl,            1-(pyridin-2-yl)-cyclobutyl,            1-(1-oxy-pyridin-2-yl)-cyclopropyl);    -   and R^(N2) independently represents hydrogen or methyl.        15) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 10), wherein R¹        represents R^(N1)R^(N2)N—, wherein    -   R^(N1) represents        -   hydrogen;        -   methyl, ethyl, isopropyl, isobutyl, tert.-butyl, or            1,2,2-trimethyl-propyl;        -   2-hydroxy-ethyl, 2-hydroxy-1-methyl-ethyl,            2-hydroxy-1,1-dimethyl-ethyl, 2-methoxy-ethyl,            3-methoxy-propyl, 2-ethoxy-ethyl, 2-ethoxy-1-methyl-ethyl,            2-methoxy-1,1-dimethyl-ethyl, 3-methoxy-1,1-dimethyl-propyl,            2-(2-hydroxy-ethoxy)-ethyl carbamoyl-methyl,            2-methanesulfonyl-1,1-dimethyl-ethyl,            1-cyano-1-methyl-ethyl, 2-dimethylamino-ethyl, or            2-trifluoromethoxy-ethyl;        -   1-methyl-prop-2-ynyl;        -   2-fluoro-ethyl, 2,2-difluoro-ethyl, 2-fluoro-1-methyl-ethyl,            2-fluoro-1,1-dimethyl-ethyl, 2,2-difluoro-1-methyl-ethyl, or            3,3,3-trifluoro-1,1-dimethyl-propyl;        -   methoxy;        -   2-(2-oxo-pyrrolidin-1-yl)-ethyl;        -   cyclopropyl, cyclopentyl, 1-methyl-cyclopropyl,            1-methyl-cyclobutyl, 1-cyclopropyl-cyclopropan-1-yl,            1-cyclobutyl-ethyl, 3-methyl-tetrahydrofuran-3-yl,            tetrahydrofuran-3-yl-methyl, tetrahydrofuran-2-yl-methyl,            1-tetrahydrofuran-2-yl-ethyl, oxetan-3-yl-methyl, or            3,3-difluoro-1-methyl-cyclobutyl,        -   1-(ethoxycarbonyl)-cyclopropyl, or 1-cyano-cyclobutyl;        -   phenyl, benzyl, 1-phenyl-ethyl, 2-(2-chloro-phenyl)-ethyl,            2-(4-fluoro-phenyl)-ethyl, 2-(2-methyl-phenyl)-ethyl,            2-(3-methyl-phenyl)-ethyl, 2-(4-methyl-phenyl)-ethyl,            2-(2-methoxy-phenyl)-ethyl, 2-phenyl-propyl,            2-hydroxy-1-phenyl-ethyl, 2-hydroxy-2-phenyl-ethyl, or            2-phenyl-cyclopropyl,        -   1-(3-bromo-phenyl)-ethyl, 1-phenyl-cyclopropyl,            1-phenyl-cyclobutyl, 2-phenyl-cyclobutyl,            1-(3-chloro-phenyl)-cyclopropyl,            1-(4-fluoro-phenyl)-cyclopropyl,            1-(3-fluoro-phenyl)-cyclopropyl,            1-(2-fluoro-phenyl)-cyclopropyl,            1-(2-methyl-phenyl)-cyclopropyl,            1-(2-hydroxy-phenyl)-cyclopropyl,            1-(2-methoxy-phenyl)-ethyl,            2-methyl-2-(2-chloro-phenyl)-propyl,            1-(4-chloro-phenyl)-cyclopropyl-methyl,            3-(3-chloro-phenyl)-oxetan-3-yl,            3-(4-fluoro-phenyl)-oxetan-3-yl,            3-(phenyl)-oxetan-3-yl-methyl, 3-(benzyl)-oxetan-3-yl,            1-(2-methoxy-phenyl)-cyclopropyl,            1-(3-methoxy-phenyl)-cyclopropyl,            1-(2-trifluoromethyl-phenyl)-cyclopropyl, or            2-ethoxy-2-oxo-1-phenylethyl;        -   4,5-dimethyl-thiazol-2-yl, 1H-imidazol-4-yl-methyl,            thiazol-2-yl-methyl, 4-methyl-thiazol-5-yl-methyl,            4-methyl-thiazol-2-yl-methyl, 5-methyl-thiazol-2-yl-methyl,            2-methyl-thiazol-4-yl-methyl, oxazol-5-yl-methyl,            1-(2H-pyrazol-3-yl)-ethyl,            (1-methyl-1H-pyrazol-3-yl)-methyl,            1-([1,2,4]oxadiazol-3-yl)-ethyl, 1-(isoxazol-3-yl)-ethyl,            3-methyl-isoxazol-5-yl-methyl,            5-methyl-isoxazol-3-yl-methyl,            1-(1H-[1,2,4]triazol-3-yl)-ethyl,            (1,5-dimethyl-1H-pyrazol-3-yl)-methyl,            (2,5-dimethyl-2H-pyrazol-3-yl)-methyl,            (3-ethyl-([1,2,4]oxadiazol-5-yl)-methyl,            1-(5-methyl-([1,3,4]oxadiazol-2-yl)-ethyl,            1-methyl-1-(1-methyl-1H-pyrazol-4-yl)-ethyl, or            1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl; or        -   pyridin-3-yl, pyridin-2-yl-methyl, pyridin-3-yl-methyl,            pyridin-4-yl-methyl, pyrimidin-2-yl-methyl,            pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl,            1-(pyridin-2-yl)-ethyl, 1-(pyridin-3-yl)-ethyl,            2-(pyridin-2-yl)-ethyl, 1-methyl-1-(pyridin-2-yl)-ethyl,            1-(pyrazin-2-yl)-ethyl, 1-(pyrimidin-4-yl)-ethyl,            1-(5-fluoro-pyrimidin-2-yl)-ethyl,            1-(3-fluoro-pyridin-2-yl)-ethyl,            1-(5-fluoro-pyridin-2-yl)-ethyl,            1-(6-methyl-pyridin-2-yl)-ethyl,            2-hydroxy-1-(pyridin-2-yl)-ethyl,            1-(1-oxy-pyridin-2-yl)-ethyl, 1-(pyridin-2-yl)-cyclopropyl,            1-(pyridin-4-yl)-cyclopropyl, 1-(pyrazin-2-yl)-cyclopropyl,            1-(pyridazin-3-yl)-cyclopropyl,            1-(pyrimidin-2-yl)-cyclopropyl,            1-(5-fluoro-pyridin-2-yl)-cyclopropyl,            1-(3,5-difluoro-pyridin-2-yl)-ethyl,            2,2,2-trifluoro-1-(pyridin-2-yl)-ethyl, or            1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl; or        -   (6-methyl-pyridin-2-yl)-methyl, 1-(pyrimidin-2-yl)-ethyl,            1-methyl-1-(pyrimidin-2-yl)-ethyl,            1-(pyrimidin-4-yl)-cyclopropyl,            2-(pyrimidin-2-yl)-cyclobutyl,            2-(pyrimidin-2-yl)-cyclopentyl,            1-(1-oxy-pyrimidin-2-yl)-cyclopropyl,            1-(3-fluoro-pyridin-2-yl)-cyclopropyl,            [1-(pyridin-2-yl)-cyclopropyl]-methyl,            1-(pyridin-2-yl)-cyclobutyl,            1-(1-oxy-pyridin-2-yl)-cyclopropyl,            2-methyl-2-(pyridin-2-yl)-propyl, or            2-methyl-2-(3-methyl-pyridin-2-yl)-propyl;    -   and R^(N2) independently represents hydrogen, methyl, ethyl,        isopropyl, or 2-fluoro-ethyl;    -   or R^(N1) and R^(N2) together with the nitrogen atom to which        they are attached to form a 4- to 6-membered ring selected from        azetidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl,        3-fluoro-azetidin-1-yl, 3,3-difluoro-azetidin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-phenyl-pyrrolidin-1-yl,        3-(pyridin-2-yl)-pyrrolidin-1-yl.        16) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 15), wherein R²        represents    -   hydrogen;    -   (C₁₋₆)alkyl (especially ethyl, isopropyl, isobutyl, tert.-butyl,        2,2-dimethylpropyl, 3-methyl-butyl, 3,3-dimethylbutyl);    -   (C₂₋₆)alkyl which is mono-substituted with (C₁₋₃)alkoxy        (especially methoxy), or hydroxy; (especially 2-hydroxyethyl,        2-methoxy-ethyl, 2-hydroxy-1-methyl-propyl);    -   (C₃₋₈)cycloalkyl-(C₁₋₃)alkyl, wherein the (C₃₋₈)cycloalkyl is        unsubstituted; or mono-substituted wherein the substituent is        (C₁₋₃)alkyl (especially methyl), fluoro, or (C₁₋₃)fluoroalkyl        (especially difluoromethyl); or di-substituted with fluoro;    -   (especially cyclopropylmethyl, cyclobutylmethyl,        cyclopentylmethyl, 1-cyclopropyl-ethyl,        (1-methyl-cyclopropyl)-methyl, (1-methyl-cyclobutyl)-methyl,        2-cyclopropyl-ethyl, (1-fluoro-cyclopropyl)-methyl,        (2,2-difluorocyclopropyl)-methyl,        (3,3-difluorocyclobutyl)-methyl,        (1-difluoromethyl-cyclopropyl)-methyl);    -   (C₃₋₈)cycloalkyl, wherein the (C₃₋₈)cycloalkyl is unsubstituted,        or mono- or di-substituted wherein the substituents are        independently selected from (C₁₋₃)alkyl (especially methyl),        fluoro, hydroxy, hydroxy-(C₁₋₃)alkyl (especially        hydroxy-methyl), or (C₁₋₃)alkoxy (especially methoxy);    -   (especially cyclobutyl, 2-methylcyclobutyl,        2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl,        cyclohexyl, spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl,        bicyclo[2.2.1]hept-2-yl, 2-methylcyclopentyl,        2-(hydroxymethyl)-cyclopentyl, 3,3-dimethylcyclopentyl,        2-ethylcyclopentyl, 3,3-dimethylcyclohexyl, 2-fluoro-cyclohexyl,        4-fluoro-cyclohexyl, 4,4-difluoro-cyclohexyl,        2-hydroxy-cyclohexyl, 2-methoxy-cyclohexyl,        3-methoxy-cyclohexyl, spiro[2.3]hex-5-yl,        bicyclo[3.1.0]hex-3-yl, 3,3-difluorocyclobutyl);    -   (C₃₋₈)cycloalkenyl-(C₁₋₃)alkyl (especially        cyclopenten-1-ylmethyl); or    -   benzyl wherein the phenyl ring of said benzyl is unsubstituted,        or mono-substituted with halogen (especially benzyl,        2-chloro-benzyl, 2-fluoro-benzyl, 4-fluoro-benzyl).        17) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 15), wherein R²        represents    -   (C₃₋₈)cycloalkyl-(C₁₋₃)alkyl, wherein the (C₃₋₈)cycloalkyl is        unsubstituted; or mono-substituted wherein the substituent is        (C₁₋₃)alkyl (especially methyl), fluoro, or (C₁₋₃)fluoroalkyl        (especially difluoromethyl); or di-substituted with fluoro;        (especially cyclopropylmethyl, cyclobutylmethyl,        cyclopentylmethyl, 1-cyclopropyl-ethyl,        (1-methyl-cyclopropyl)-methyl, (1-methyl-cyclobutyl)-methyl,        2-cyclopropyl-ethyl, (1-fluoro-cyclopropyl)-methyl,        (2,2-difluorocyclopropyl)-methyl,        (3,3-difluorocyclobutyl)-methyl,        (1-difluoromethyl-cyclopropyl)-methyl); or    -   (C₃₋₈)cycloalkyl, wherein the (C₃₋₈)cycloalkyl is unsubstituted,        or mono- or di-substituted wherein the substituents are        independently selected from (C₁₋₃)alkyl (especially methyl), or        fluoro; (especially cyclobutyl, 2-methylcyclobutyl,        2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl,        cyclohexyl, spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl,        bicyclo[2.2.1]hept-2-yl, 2-methylcyclopentyl,        3,3-dimethylcyclopentyl, 2-ethylcyclopentyl,        3,3-dimethylcyclohexyl, 2-fluoro-cyclohexyl,        4-fluoro-cyclohexyl, 4,4-difluoro-cyclohexyl,        spiro[2.3]hex-5-yl, bicyclo[3.1.0]hex-3-yl,        3,3-difluorocyclobutyl).        18) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 15), wherein R²        represents    -   unsubstituted (C₃₋₈)cycloalkyl-(C₁₋₃)alkyl (especially        cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,        1-cyclopropyl-ethyl, 2-cyclopropyl-ethyl); or    -   unsubstituted (C₃₋₆)cycloalkyl (especially cyclobutyl,        cyclopentyl, cyclohexyl); or    -   (C₃₋₈)cycloalkyl, wherein the (C₃₋₈)cycloalkyl is di-substituted        with fluoro (especially 3,3-difluorocyclobutyl); or    -   (C₃₋₈)cycloalkyl-(C₁₋₃)alkyl; wherein the (C₃₋₈)cycloalkyl is        mono-substituted with methyl, fluoro, or (C₁)fluoroalkyl        (especially difluoromethyl); or di-substituted with fluoro        (especially (1-methyl-cyclopropyl)-methyl,        (1-methyl-cyclobutyl)-methyl, (1-fluoro-cyclopropyl)-methyl,        (2,2-difluorocyclopropyl)-methyl,        (3,3-difluorocyclobutyl)-methyl,        (1-difluoromethyl-cyclopropyl)-methyl).        19) A further embodiment relates to the compounds of formula (I)        according to any one of embodiments 1) to 15), wherein R²        represents    -   hydrogen;    -   ethyl, isopropyl, 2,2-dimethylpropyl, 3-methyl-butyl,        3,3-dimethylbutyl;    -   isobutyl, tert.-butyl;    -   2-hydroxyethyl, 2-methoxy-ethyl, 2-hydroxy-1-methyl-propyl;    -   allyl;    -   cyano-methyl;    -   3-fluoro-propyl;    -   cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,        1-cyclopropyl-ethyl, (1-methyl-cyclopropyl)-methyl,        (1-methyl-cyclobutyl)-methyl, 2-cyclopropyl-ethyl;    -   (1-fluoro-cyclopropyl)-methyl, (2,2-difluorocyclopropyl)-methyl,        (3,3-difluorocyclobutyl)-methyl,        (1-difluoromethyl-cyclopropyl)-methyl;    -   cyclobutyl, cyclopentyl, cyclohexyl;    -   2-methylcyclobutyl, 2,2-dimethylcyclobutyl,        3,3-dimethylcyclobutyl;    -   2-methylcyclopentyl, 2-(hydroxymethyl)-cyclopentyl,        3,3-dimethylcyclopentyl, 2-ethylcyclopentyl,        3,3-dimethylcyclohexyl, 2-fluoro-cyclohexyl,        4-fluoro-cyclohexyl, 4,4-difluoro-cyclohexyl,        2-hydroxy-cyclohexyl, 2-methoxy-cyclohexyl,        3-methoxy-cyclohexyl;    -   3,3-difluorocyclobutyl;    -   spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl,        bicyclo[2.2.1]hept-2-yl;    -   spiro[2.3]hex-5-yl, bicyclo[3.1.0]hex-3-yl;    -   thietan-3-yl;    -   cyclopenten-1-ylmethyl; or    -   benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, or 4-fluoro-benzyl.        20) The invention, thus, especially relates to compounds of the        formula (I) as defined in embodiment 1), and to such compounds        further limited by the characteristics of any one of        embodiments 2) to 19), under consideration of their respective        dependencies; to pharmaceutically acceptable salts thereof; and        to the use of such compounds as medicaments especially in the        prevention/prophylaxis or treatment of disorders relating to the        CXCR7 receptor or its ligands as described herein, alone, or, as        for example in the case of cancer (especially in the case of        malignant glioma, in particular a glioblastoma multiforme;        pancreatic cancer, in particular pancreatic ductal        adenocarcinoma; papillary thyroid carcinoma; lung metastasis;        melanoma; lung cancer; metastatic cancers; hepatocellular        carcinoma; breast cancer; colon cancer; head and neck cancer),        optionally in combination with one or more therapeutic agents        and/or radiotherapy and/or targeted therapy. For avoidance of        any doubt, especially the following embodiments relating to the        compounds of formula (I) are thus possible and intended and        herewith specifically disclosed in individualized form: 1, 3+1,        4+1, 4+3+1, 5+1, 5+3+1, 5+4+1, 5+4+3+1, 7+1, 7+3+1, 7+4+1,        7+4+3+1, 8+1, 8+3+1, 8+4+1, 8+4+3+1, 9+1, 9+3+1, 9+4+1, 9+4+3+1,        9+5+1, 9+5+3+1, 9+5+4+1, 9+5+4+3+1, 9+7+1, 9+7+3+1, 9+7+4+1,        9+7+4+3+1, 9+8+1, 9+8+3+1, 9+8+4+1, 9+8+4+3+1, 10+1, 10+3+1,        10+4+1, 10+4+3+1, 10+5+1, 10+5+3+1, 10+5+4+1, 10+5+4+3+1,        10+7+1, 10+7+3+1, 10+7+4+1, 10+7+4+3+1, 10+8+1, 10+8+3+1,        10+8+4+1, 10+8+4+3+1, 11+1, 11+3+1, 11+4+1, 11+4+3+1, 11+5+1,        11+5+3+1, 11+5+4+1, 11+5+4+3+1, 11+7+1, 11+7+3+1, 11+7+4+1,        11+7+4+3+1, 11+8+1, 11+8+3+1, 11+8+4+1, 11+8+4+3+1, 11+9+1,        11+9+3+1, 11+9+4+1, 11+9+4+3+1, 11+9+5+1, 11+9+5+3+1,        11+9+5+4+1, 11+9+5+4+3+1, 11+9+7+1, 11+9+7+3+1, 11+9+7+4+1,        11+9+7+4+3+1, 11+9+8+1, 11+9+8+3+1, 11+9+8+4+1, 11+9+8+4+3+1,        11+10+1, 11+10+3+1, 11+10+4+1, 11+10+4+3+1, 11+10+5+1,        11+10+5+3+1, 11+10+5+4+1, 11+10+5+4+3+1, 11+10+7+1, 11+10+7+3+1,        11+10+7+4+1, 11+10+7+4+3+1, 11+10+8+1, 11+10+8+3+1, 11+10+8+4+1,        11+10+8+4+3+1, 12+1, 12+3+1, 12+4+1, 12+4+3+1, 12+5+1, 12+5+3+1,        12+5+4+1, 12+5+4+3+1, 12+7+1, 12+7+3+1, 12+7+4+1, 12+7+4+3+1,        12+8+1, 12+8+3+1, 12+8+4+1, 12+8+4+3+1, 12+9+1, 12+9+3+1,        12+9+4+1, 12+9+4+3+1, 12+9+5+1, 12+9+5+3+1, 12+9+5+4+1,        12+9+5+4+3+1, 12+9+7+1, 12+9+7+3+1, 12+9+7+4+1, 12+9+7+4+3+1,        12+9+8+1, 12+9+8+3+1, 12+9+8+4+1, 12+9+8+4+3+1, 12+10+1,        12+10+3+1, 12+10+4+1, 12+10+4+3+1, 12+10+5+1, 12+10+5+3+1,        12+10+5+4+1, 12+10+5+4+3+1, 12+10+7+1, 12+10+7+3+1, 12+10+7+4+1,        12+10+7+4+3+1, 12+10+8+1, 12+10+8+3+1, 12+10+8+4+1,        12+10+8+4+3+1, 13+1, 13+3+1, 13+4+1, 13+4+3+1, 13+5+1, 13+5+3+1,        13+5+4+1, 13+5+4+3+1, 13+7+1, 13+7+3+1, 13+7+4+1, 13+7+4+3+1,        13+8+1, 13+8+3+1, 13+8+4+1, 13+8+4+3+1, 13+9+1, 13+9+3+1,        13+9+4+1, 13+9+4+3+1, 13+9+5+1, 13+9+5+3+1, 13+9+5+4+1,        13+9+5+4+3+1, 13+9+7+1, 13+9+7+3+1, 13+9+7+4+1, 13+9+7+4+3+1,        13+9+8+1, 13+9+8+3+1, 13+9+8+4+1, 13+9+8+4+3+1, 13+10+1,        13+10+3+1, 13+10+4+1, 13+10+4+3+1, 13+10+5+1, 13+10+5+3+1,        13+10+5+4+1, 13+10+5+4+3+1, 13+10+7+1, 13+10+7+3+1, 13+10+7+4+1,        13+10+7+4+3+1, 13+10+8+1, 13+10+8+3+1, 13+10+8+4+1,        13+10+8+4+3+1, 14+1, 14+3+1, 14+4+1, 14+4+3+1, 14+5+1, 14+5+3+1,        14+5+4+1, 14+5+4+3+1, 14+7+1, 14+7+3+1, 14+7+4+1, 14+7+4+3+1,        14+8+1, 14+8+3+1, 14+8+4+1, 14+8+4+3+1, 14+9+1, 14+9+3+1,        14+9+4+1, 14+9+4+3+1, 14+9+5+1, 14+9+5+3+1, 14+9+5+4+1,        14+9+5+4+3+1, 14+9+7+1, 14+9+7+3+1, 14+9+7+4+1, 14+9+7+4+3+1,        14+9+8+1, 14+9+8+3+1, 14+9+8+4+1, 14+9+8+4+3+1, 14+10+1,        14+10+3+1, 14+10+4+1, 14+10+4+3+1, 14+10+5+1, 14+10+5+3+1,        14+10+5+4+1, 14+10+5+4+3+1, 14+10+7+1, 14+10+7+3+1, 14+10+7+4+1,        14+10+7+4+3+1, 14+10+8+1, 14+10+8+3+1, 14+10+8+4+1,        14+10+8+4+3+1, 15+1, 15+3+1, 15+4+1, 15+4+3+1, 15+5+1, 15+5+3+1,        15+5+4+1, 15+5+4+3+1, 15+7+1, 15+7+3+1, 15+7+4+1, 15+7+4+3+1,        15+8+1, 15+8+3+1, 15+8+4+1, 15+8+4+3+1, 15+9+1, 15+9+3+1,        15+9+4+1, 15+9+4+3+1, 15+9+5+1, 15+9+5+3+1, 15+9+5+4+1,        15+9+5+4+3+1, 15+9+7+1, 15+9+7+3+1, 15+9+7+4+1, 15+9+7+4+3+1,        15+9+8+1, 15+9+8+3+1, 15+9+8+4+1, 15+9+8+4+3+1, 15+10+1,        15+10+3+1, 15+10+4+1, 15+10+4+3+1, 15+10+5+1, 15+10+5+3+1,        15+10+5+4+1, 15+10+5+4+3+1, 15+10+7+1, 15+10+7+3+1, 15+10+7+4+1,        15+10+7+4+3+1, 15+10+8+1, 15+10+8+3+1, 15+10+8+4+1,        15+10+8+4+3+1, 17+1, 17+3+1, 17+4+1, 17+4+3+1, 17+5+1, 17+5+3+1,        17+5+4+1, 17+5+4+3+1, 17+7+1, 17+7+3+1, 17+7+4+1, 17+7+4+3+1,        17+8+1, 17+8+3+1, 17+8+4+1, 17+8+4+3+1, 17+9+1, 17+9+3+1,        17+9+4+1, 17+9+4+3+1, 17+9+5+1, 17+9+5+3+1, 17+9+5+4+1,        17+9+5+4+3+1, 17+9+7+1, 17+9+7+3+1, 17+9+7+4+1, 17+9+7+4+3+1,        17+9+8+1, 17+9+8+3+1, 17+9+8+4+1, 17+9+8+4+3+1, 17+10+1,        17+10+3+1, 17+10+4+1, 17+10+4+3+1, 17+10+5+1, 17+10+5+3+1,        17+10+5+4+1, 17+10+5+4+3+1, 17+10+7+1, 17+10+7+3+1, 17+10+7+4+1,        17+10+7+4+3+1, 17+10+8+1, 17+10+8+3+1, 17+10+8+4+1,        17+10+8+4+3+1, 17+11+1, 17+11+3+1, 17+11+4+1, 17+11+4+3+1,        17+11+5+1, 17+11+5+3+1, 17+11+5+4+1, 17+11+5+4+3+1, 17+11+7+1,        17+11+7+3+1, 17+11+7+4+1, 17+11+7+4+3+1, 17+11+8+1, 17+11+8+3+1,        17+11+8+4+1, 17+11+8+4+3+1, 17+11+9+1, 17+11+9+3+1, 17+11+9+4+1,        17+11+9+4+3+1, 17+11+9+5+1, 17+11+9+5+3+1, 17+11+9+5+4+1,        17+11+9+5+4+3+1, 17+11+9+7+1, 17+11+9+7+3+1, 17+11+9+7+4+1,        17+11+9+7+4+3+1, 17+11+9+8+1, 17+11+9+8+3+1, 17+11+9+8+4+1,        17+11+9+8+4+3+1, 17+11+10+1, 17+11+10+3+1, 17+11+10+4+1,        17+11+10+4+3+1, 17+11+10+5+1, 17+11+10+5+3+1, 17+11+10+5+4+1,        17+11+10+5+4+3+1, 17+11+10+7+1, 17+11+10+7+3+1, 17+11+10+7+4+1,        17+11+10+7+4+3+1, 17+11+10+8+1, 17+11+10+8+3+1, 17+11+10+8+4+1,        17+11+10+8+4+3+1, 17+12+1, 17+12+3+1, 17+12+4+1, 17+12+4+3+1,        17+12+5+1, 17+12+5+3+1, 17+12+5+4+1, 17+12+5+4+3+1, 17+12+7+1,        17+12+7+3+1, 17+12+7+4+1, 17+12+7+4+3+1, 17+12+8+1, 17+12+8+3+1,        17+12+8+4+1, 17+12+8+4+3+1, 17+12+9+1, 17+12+9+3+1, 17+12+9+4+1,        17+12+9+4+3+1, 17+12+9+5+1, 17+12+9+5+3+1, 17+12+9+5+4+1,        17+12+9+5+4+3+1, 17+12+9+7+1, 17+12+9+7+3+1, 17+12+9+7+4+1,        17+12+9+7+4+3+1, 17+12+9+8+1, 17+12+9+8+3+1, 17+12+9+8+4+1,        17+12+9+8+4+3+1, 17+12+10+1, 17+12+10+3+1, 17+12+10+4+1,        17+12+10+4+3+1, 17+12+10+5+1, 17+12+10+5+3+1, 17+12+10+5+4+1,        17+12+10+5+4+3+1, 17+12+10+7+1, 17+12+10+7+3+1, 17+12+10+7+4+1,        17+12+10+7+4+3+1, 17+12+10+8+1, 17+12+10+8+3+1, 17+12+10+8+4+1,        17+12+10+8+4+3+1, 17+13+1, 17+13+3+1, 17+13+4+1, 17+13+4+3+1,        17+13+5+1, 17+13+5+3+1, 17+13+5+4+1, 17+13+5+4+3+1, 17+13+7+1,        17+13+7+3+1, 17+13+7+4+1, 17+13+7+4+3+1, 17+13+8+1, 17+13+8+3+1,        17+13+8+4+1, 17+13+8+4+3+1, 17+13+9+1, 17+13+9+3+1, 17+13+9+4+1,        17+13+9+4+3+1, 17+13+9+5+1, 17+13+9+5+3+1, 17+13+9+5+4+1,        17+13+9+5+4+3+1, 17+13+9+7+1, 17+13+9+7+3+1, 17+13+9+7+4+1,        17+13+9+7+4+3+1, 17+13+9+8+1, 17+13+9+8+3+1, 17+13+9+8+4+1,        17+13+9+8+4+3+1, 17+13+10+1, 17+13+10+3+1, 17+13+10+4+1,        17+13+10+4+3+1, 17+13+10+5+1, 17+13+10+5+3+1, 17+13+10+5+4+1,        17+13+10+5+4+3+1, 17+13+10+7+1, 17+13+10+7+3+1, 17+13+10+7+4+1,        17+13+10+7+4+3+1, 17+13+10+8+1, 17+13+10+8+3+1, 17+13+10+8+4+1,        17+13+10+8+4+3+1, 17+14+1, 17+14+3+1, 17+14+4+1, 17+14+4+3+1,        17+14+5+1, 17+14+5+3+1, 17+14+5+4+1, 17+14+5+4+3+1, 17+14+7+1,        17+14+7+3+1, 17+14+7+4+1, 17+14+7+4+3+1, 17+14+8+1, 17+14+8+3+1,        17+14+8+4+1, 17+14+8+4+3+1, 17+14+9+1, 17+14+9+3+1, 17+14+9+4+1,        17+14+9+4+3+1, 17+14+9+5+1, 17+14+9+5+3+1, 17+14+9+5+4+1,        17+14+9+5+4+3+1, 17+14+9+7+1, 17+14+9+7+3+1, 17+14+9+7+4+1,        17+14+9+7+4+3+1, 17+14+9+8+1, 17+14+9+8+3+1, 17+14+9+8+4+1,        17+14+9+8+4+3+1, 17+14+10+1, 17+14+10+3+1, 17+14+10+4+1,        17+14+10+4+3+1, 17+14+10+5+1, 17+14+10+5+3+1, 17+14+10+5+4+1,        17+14+10+5+4+3+1, 17+14+10+7+1, 17+14+10+7+3+1, 17+14+10+7+4+1,        17+14+10+7+4+3+1, 17+14+10+8+1, 17+14+10+8+3+1, 17+14+10+8+4+1,        17+14+10+8+4+3+1, 17+15+1, 17+15+3+1, 17+15+4+1, 17+15+4+3+1,        17+15+5+1, 17+15+5+3+1, 17+15+5+4+1, 17+15+5+4+3+1, 17+15+7+1,        17+15+7+3+1, 17+15+7+4+1, 17+15+7+4+3+1, 17+15+8+1, 17+15+8+3+1,        17+15+8+4+1, 17+15+8+4+3+1, 17+15+9+1, 17+15+9+3+1, 17+15+9+4+1,        17+15+9+4+3+1, 17+15+9+5+1, 17+15+9+5+3+1, 17+15+9+5+4+1,        17+15+9+5+4+3+1, 17+15+9+7+1, 17+15+9+7+3+1, 17+15+9+7+4+1,        17+15+9+7+4+3+1, 17+15+9+8+1, 17+15+9+8+3+1, 17+15+9+8+4+1,        17+15+9+8+4+3+1, 17+15+10+1, 17+15+10+3+1, 17+15+10+4+1,        17+15+10+4+3+1, 17+15+10+5+1, 17+15+10+5+3+1, 17+15+10+5+4+1,        17+15+10+5+4+3+1, 17+15+10+7+1, 17+15+10+7+3+1, 17+15+10+7+4+1,        17+15+10+7+4+3+1, 17+15+10+8+1, 17+15+10+8+3+1, 17+15+10+8+4+1,        17+15+10+8+4+3+1, 18+1, 18+3+1, 18+4+1, 18+4+3+1, 18+5+1,        18+5+3+1, 18+5+4+1, 18+5+4+3+1, 18+7+1, 18+7+3+1, 18+7+4+1,        18+7+4+3+1, 18+8+1, 18+8+3+1, 18+8+4+1, 18+8+4+3+1, 18+9+1,        18+9+3+1, 18+9+4+1, 18+9+4+3+1, 18+9+5+1, 18+9+5+3+1,        18+9+5+4+1, 18+9+5+4+3+1, 18+9+7+1, 18+9+7+3+1, 18+9+7+4+1,        18+9+7+4+3+1, 18+9+8+1, 18+9+8+3+1, 18+9+8+4+1, 18+9+8+4+3+1,        18+10+1, 18+10+3+1, 18+10+4+1, 18+10+4+3+1, 18+10+5+1,        18+10+5+3+1, 18+10+5+4+1, 18+10+5+4+3+1, 18+10+7+1, 18+10+7+3+1,        18+10+7+4+1, 18+10+7+4+3+1, 18+10+8+1, 18+10+8+3+1, 18+10+8+4+1,        18+10+8+4+3+1, 18+11+1, 18+11+3+1, 18+11+4+1, 18+11+4+3+1,        18+11+5+1, 18+11+5+3+1, 18+11+5+4+1, 18+11+5+4+3+1, 18+11+7+1,        18+11+7+3+1, 18+11+7+4+1, 18+11+7+4+3+1, 18+11+8+1, 18+11+8+3+1,        18+11+8+4+1, 18+11+8+4+3+1, 18+11+9+1, 18+11+9+3+1, 18+11+9+4+1,        18+11+9+4+3+1, 18+11+9+5+1, 18+11+9+5+3+1, 18+11+9+5+4+1,        18+11+9+5+4+3+1, 18+11+9+7+1, 18+11+9+7+3+1, 18+11+9+7+4+1,        18+11+9+7+4+3+1, 18+11+9+8+1, 18+11+9+8+3+1, 18+11+9+8+4+1,        18+11+9+8+4+3+1, 18+11+10+1, 18+11+10+3+1, 18+11+10+4+1,        18+11+10+4+3+1, 18+11+10+5+1, 18+11+10+5+3+1, 18+11+10+5+4+1,        18+11+10+5+4+3+1, 18+11+10+7+1, 18+11+10+7+3+1, 18+11+10+7+4+1,        18+11+10+7+4+3+1, 18+11+10+8+1, 18+11+10+8+3+1, 18+11+10+8+4+1,        18+11+10+8+4+3+1, 18+12+1, 18+12+3+1, 18+12+4+1, 18+12+4+3+1,        18+12+5+1, 18+12+5+3+1, 18+12+5+4+1, 18+12+5+4+3+1, 18+12+7+1,        18+12+7+3+1, 18+12+7+4+1, 18+12+7+4+3+1, 18+12+8+1, 18+12+8+3+1,        18+12+8+4+1, 18+12+8+4+3+1, 18+12+9+1, 18+12+9+3+1, 18+12+9+4+1,        18+12+9+4+3+1, 18+12+9+5+1, 18+12+9+5+3+1, 18+12+9+5+4+1,        18+12+9+5+4+3+1, 18+12+9+7+1, 18+12+9+7+3+1, 18+12+9+7+4+1,        18+12+9+7+4+3+1, 18+12+9+8+1, 18+12+9+8+3+1, 18+12+9+8+4+1,        18+12+9+8+4+3+1, 18+12+10+1, 18+12+10+3+1, 18+12+10+4+1,        18+12+10+4+3+1, 18+12+10+5+1, 18+12+10+5+3+1, 18+12+10+5+4+1,        18+12+10+5+4+3+1, 18+12+10+7+1, 18+12+10+7+3+1, 18+12+10+7+4+1,        18+12+10+7+4+3+1, 18+12+10+8+1, 18+12+10+8+3+1, 18+12+10+8+4+1,        18+12+10+8+4+3+1, 18+13+1, 18+13+3+1, 18+13+4+1, 18+13+4+3+1,        18+13+5+1, 18+13+5+3+1, 18+13+5+4+1, 18+13+5+4+3+1, 18+13+7+1,        18+13+7+3+1, 18+13+7+4+1, 18+13+7+4+3+1, 18+13+8+1, 18+13+8+3+1,        18+13+8+4+1, 18+13+8+4+3+1, 18+13+9+1, 18+13+9+3+1, 18+13+9+4+1,        18+13+9+4+3+1, 18+13+9+5+1, 18+13+9+5+3+1, 18+13+9+5+4+1,        18+13+9+5+4+3+1, 18+13+9+7+1, 18+13+9+7+3+1, 18+13+9+7+4+1,        18+13+9+7+4+3+1, 18+13+9+8+1, 18+13+9+8+3+1, 18+13+9+8+4+1,        18+13+9+8+4+3+1, 18+13+10+1, 18+13+10+3+1, 18+13+10+4+1,        18+13+10+4+3+1, 18+13+10+5+1, 18+13+10+5+3+1, 18+13+10+5+4+1,        18+13+10+5+4+3+1, 18+13+10+7+1, 18+13+10+7+3+1, 18+13+10+7+4+1,        18+13+10+7+4+3+1, 18+13+10+8+1, 18+13+10+8+3+1, 18+13+10+8+4+1,        18+13+10+8+4+3+1, 18+14+1, 18+14+3+1, 18+14+4+1, 18+14+4+3+1,        18+14+5+1, 18+14+5+3+1, 18+14+5+4+1, 18+14+5+4+3+1, 18+14+7+1,        18+14+7+3+1, 18+14+7+4+1, 18+14+7+4+3+1, 18+14+8+1, 18+14+8+3+1,        18+14+8+4+1, 18+14+8+4+3+1, 18+14+9+1, 18+14+9+3+1, 18+14+9+4+1,        18+14+9+4+3+1, 18+14+9+5+1, 18+14+9+5+3+1, 18+14+9+5+4+1,        18+14+9+5+4+3+1, 18+14+9+7+1, 18+14+9+7+3+1, 18+14+9+7+4+1,        18+14+9+7+4+3+1, 18+14+9+8+1, 18+14+9+8+3+1, 18+14+9+8+4+1,        18+14+9+8+4+3+1, 18+14+10+1, 18+14+10+3+1, 18+14+10+4+1,        18+14+10+4+3+1, 18+14+10+5+1, 18+14+10+5+3+1, 18+14+10+5+4+1,        18+14+10+5+4+3+1, 18+14+10+7+1, 18+14+10+7+3+1, 18+14+10+7+4+1,        18+14+10+7+4+3+1, 18+14+10+8+1, 18+14+10+8+3+1, 18+14+10+8+4+1,        18+14+10+8+4+3+1, 18+15+1, 18+15+3+1, 18+15+4+1, 18+15+4+3+1,        18+15+5+1, 18+15+5+3+1, 18+15+5+4+1, 18+15+5+4+3+1, 18+15+7+1,        18+15+7+3+1, 18+15+7+4+1, 18+15+7+4+3+1, 18+15+8+1, 18+15+8+3+1,        18+15+8+4+1, 18+15+8+4+3+1, 18+15+9+1, 18+15+9+3+1, 18+15+9+4+1,        18+15+9+4+3+1, 18+15+9+5+1, 18+15+9+5+3+1, 18+15+9+5+4+1,        18+15+9+5+4+3+1, 18+15+9+7+1, 18+15+9+7+3+1, 18+15+9+7+4+1,        18+15+9+7+4+3+1, 18+15+9+8+1, 18+15+9+8+3+1, 18+15+9+8+4+1,        18+15+9+8+4+3+1, 18+15+10+1, 18+15+10+3+1, 18+15+10+4+1,        18+15+10+4+3+1, 18+15+10+5+1, 18+15+10+5+3+1, 18+15+10+5+4+1,        18+15+10+5+4+3+1, 18+15+10+7+1, 18+15+10+7+3+1, 18+15+10+7+4+1,        18+15+10+7+4+3+1, 18+15+10+8+1, 18+15+10+8+3+1, 18+15+10+8+4+1,        18+15+10+8+4+3+1, 19+1, 19+3+1, 19+4+1, 19+4+3+1, 19+5+1,        19+5+3+1, 19+5+4+1, 19+5+4+3+1, 19+7+1, 19+7+3+1, 19+7+4+1,        19+7+4+3+1, 19+8+1, 19+8+3+1, 19+8+4+1, 19+8+4+3+1, 19+9+1,        19+9+3+1, 19+9+4+1, 19+9+4+3+1, 19+9+5+1, 19+9+5+3+1,        19+9+5+4+1, 19+9+5+4+3+1, 19+9+7+1, 19+9+7+3+1, 19+9+7+4+1,        19+9+7+4+3+1, 19+9+8+1, 19+9+8+3+1, 19+9+8+4+1, 19+9+8+4+3+1,        19+10+1, 19+10+3+1, 19+10+4+1, 19+10+4+3+1, 19+10+5+1,        19+10+5+3+1, 19+10+5+4+1, 19+10+5+4+3+1, 19+10+7+1, 19+10+7+3+1,        19+10+7+4+1, 19+10+7+4+3+1, 19+10+8+1, 19+10+8+3+1, 19+10+8+4+1,        19+10+8+4+3+1, 19+11+1, 19+11+3+1, 19+11+4+1, 19+11+4+3+1,        19+11+5+1, 19+11+5+3+1, 19+11+5+4+1, 19+11+5+4+3+1, 19+11+7+1,        19+11+7+3+1, 19+11+7+4+1, 19+11+7+4+3+1, 19+11+8+1, 19+11+8+3+1,        19+11+8+4+1, 19+11+8+4+3+1, 19+11+9+1, 19+11+9+3+1, 19+11+9+4+1,        19+11+9+4+3+1, 19+11+9+5+1, 19+11+9+5+3+1, 19+11+9+5+4+1,        19+11+9+5+4+3+1, 19+11+9+7+1, 19+11+9+7+3+1, 19+11+9+7+4+1,        19+11+9+7+4+3+1, 19+11+9+8+1, 19+11+9+8+3+1, 19+11+9+8+4+1,        19+11+9+8+4+3+1, 19+11+10+1, 19+11+10+3+1, 19+11+10+4+1,        19+11+10+4+3+1, 19+11+10+5+1, 19+11+10+5+3+1, 19+11+10+5+4+1,        19+11+10+5+4+3+1, 19+11+10+7+1, 19+11+10+7+3+1, 19+11+10+7+4+1,        19+11+10+7+4+3+1, 19+11+10+8+1, 19+11+10+8+3+1, 19+11+10+8+4+1,        19+11+10+8+4+3+1, 19+12+1, 19+12+3+1, 19+12+4+1, 19+12+4+3+1,        19+12+5+1, 19+12+5+3+1, 19+12+5+4+1, 19+12+5+4+3+1, 19+12+7+1,        19+12+7+3+1, 19+12+7+4+1, 19+12+7+4+3+1, 19+12+8+1, 19+12+8+3+1,        19+12+8+4+1, 19+12+8+4+3+1, 19+12+9+1, 19+12+9+3+1, 19+12+9+4+1,        19+12+9+4+3+1, 19+12+9+5+1, 19+12+9+5+3+1, 19+12+9+5+4+1,        19+12+9+5+4+3+1, 19+12+9+7+1, 19+12+9+7+3+1, 19+12+9+7+4+1,        19+12+9+7+4+3+1, 19+12+9+8+1, 19+12+9+8+3+1, 19+12+9+8+4+1,        19+12+9+8+4+3+1, 19+12+10+1, 19+12+10+3+1, 19+12+10+4+1,        19+12+10+4+3+1, 19+12+10+5+1, 19+12+10+5+3+1, 19+12+10+5+4+1,        19+12+10+5+4+3+1, 19+12+10+7+1, 19+12+10+7+3+1, 19+12+10+7+4+1,        19+12+10+7+4+3+1, 19+12+10+8+1, 19+12+10+8+3+1, 19+12+10+8+4+1,        19+12+10+8+4+3+1, 19+13+1, 19+13+3+1, 19+13+4+1, 19+13+4+3+1,        19+13+5+1, 19+13+5+3+1, 19+13+5+4+1, 19+13+5+4+3+1, 19+13+7+1,        19+13+7+3+1, 19+13+7+4+1, 19+13+7+4+3+1, 19+13+8+1, 19+13+8+3+1,        19+13+8+4+1, 19+13+8+4+3+1, 19+13+9+1, 19+13+9+3+1, 19+13+9+4+1,        19+13+9+4+3+1, 19+13+9+5+1, 19+13+9+5+3+1, 19+13+9+5+4+1,        19+13+9+5+4+3+1, 19+13+9+7+1, 19+13+9+7+3+1, 19+13+9+7+4+1,        19+13+9+7+4+3+1, 19+13+9+8+1, 19+13+9+8+3+1, 19+13+9+8+4+1,        19+13+9+8+4+3+1, 19+13+10+1, 19+13+10+3+1, 19+13+10+4+1,        19+13+10+4+3+1, 19+13+10+5+1, 19+13+10+5+3+1, 19+13+10+5+4+1,        19+13+10+5+4+3+1, 19+13+10+7+1, 19+13+10+7+3+1, 19+13+10+7+4+1,        19+13+10+7+4+3+1, 19+13+10+8+1, 19+13+10+8+3+1, 19+13+10+8+4+1,        19+13+10+8+4+3+1, 19+14+1, 19+14+3+1, 19+14+4+1, 19+14+4+3+1,        19+14+5+1, 19+14+5+3+1, 19+14+5+4+1, 19+14+5+4+3+1, 19+14+7+1,        19+14+7+3+1, 19+14+7+4+1, 19+14+7+4+3+1, 19+14+8+1, 19+14+8+3+1,        19+14+8+4+1, 19+14+8+4+3+1, 19+14+9+1, 19+14+9+3+1, 19+14+9+4+1,        19+14+9+4+3+1, 19+14+9+5+1, 19+14+9+5+3+1, 19+14+9+5+4+1,        19+14+9+5+4+3+1, 19+14+9+7+1, 19+14+9+7+3+1, 19+14+9+7+4+1,        19+14+9+7+4+3+1, 19+14+9+8+1, 19+14+9+8+3+1, 19+14+9+8+4+1,        19+14+9+8+4+3+1, 19+14+10+1, 19+14+10+3+1, 19+14+10+4+1,        19+14+10+4+3+1, 19+14+10+5+1, 19+14+10+5+3+1, 19+14+10+5+4+1,        19+14+10+5+4+3+1, 19+14+10+7+1, 19+14+10+7+3+1, 19+14+10+7+4+1,        19+14+10+7+4+3+1, 19+14+10+8+1, 19+14+10+8+3+1, 19+14+10+8+4+1,        19+14+10+8+4+3+1, 19+15+1, 19+15+3+1, 19+15+4+1, 19+15+4+3+1,        19+15+5+1, 19+15+5+3+1, 19+15+5+4+1, 19+15+5+4+3+1, 19+15+7+1,        19+15+7+3+1, 19+15+7+4+1, 19+15+7+4+3+1, 19+15+8+1, 19+15+8+3+1,        19+15+8+4+1, 19+15+8+4+3+1, 19+15+9+1, 19+15+9+3+1, 19+15+9+4+1,        19+15+9+4+3+1, 19+15+9+5+1, 19+15+9+5+3+1, 19+15+9+5+4+1,        19+15+9+5+4+3+1, 19+15+9+7+1, 19+15+9+7+3+1, 19+15+9+7+4+1,        19+15+9+7+4+3+1, 19+15+9+8+1, 19+15+9+8+3+1, 19+15+9+8+4+1,        19+15+9+8+4+3+1, 19+15+10+1, 19+15+10+3+1, 19+15+10+4+1,        19+15+10+4+3+1, 19+15+10+5+1, 19+15+10+5+3+1, 19+15+10+5+4+1,        19+15+10+5+4+3+1, 19+15+10+7+1, 19+15+10+7+3+1, 19+15+10+7+4+1,        19+15+10+7+4+3+1, 19+15+10+8+1, 19+15+10+8+3+1, 19+15+10+8+4+1,        19+15+10+8+4+3+1.

In the list above the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “18+14+8+1” forexample refers to embodiment 18) depending on embodiment 14), dependingon embodiment 8), depending on embodiment 1), i.e. embodiment“18+14+8+1” corresponds to the compounds of formula (I) according toembodiment 1) further limited by all the features of the embodiments 8),14), and 18).

21) Another embodiment relates to compounds according to embodiment 1)which are selected from the following compounds:

-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid cyclopentylamide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-1-cyclohexyl-3-(pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-hydroxy-ethyl)-methyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methoxy-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid isobutyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid isopropylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-fluoro-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid cyclopropyl-methyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid carbamoylmethyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-hydroxy-ethyl)-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-1-cyclohexyl-3-(morpholine-4-carbonyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid isopropyl-methyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-dimethylamino-ethyl)-methyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-ethoxy-ethyl)-methyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (5-methyl-thiazol-2-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-ethyl)-methyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (5-methyl-isoxazol-3-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-dimethylamino-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ethyl-methyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (pyridin-2-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2,2-difluoro-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (3-methoxy-propyl)-methyl-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-1-cyclohexyl-3-(3-hydroxy-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3-methyl-isoxazol-5-ylmethyl)-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methyl-thiazol-4-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (pyrimidin-2-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (4-methyl-thiazol-5-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (pyrimidin-4-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (oxazol-5-ylmethyl)-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-1-cyclohexyl-3-(3-fluoro-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (pyrazin-2-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-trifluoromethoxy-ethyl)-amide;-   (3R*,    4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   methyl-oxetan-3-ylmethyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-oxo-pyrrolidin-1-yl)-ethyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-methyl-1H-pyrazol-3-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1H-imidazol-4-ylmethyl)-amide;-   (3R*,    4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (tetrahydro-furan-2-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1,5-dimethyl-1H-pyrazol-3-ylmethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S,2R)-2-phenyl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R,2S)-2-phenyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S,2R)-2-phenyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R,2S)-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3-ethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide;-   (3R*,    4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (pyridin-3-ylmethyl)-amide;-   (3R*,    4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,    4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (pyridin-4-ylmethyl)-amide;-   (3R*,    4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (thiazol-2-ylmethyl)-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-1-cyclohexyl-3-(3,3-difluoro-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (tetrahydro-furan-3-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-hydroxy-ethoxy)-ethyl]-isopropyl-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-o-tolyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [2-(2-methoxy-phenyl)-ethyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [2-(2-chloro-phenyl)-ethyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [2-(4-fluoro-phenyl)-ethyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-phenyl-propyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R*,2S1-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-p-tolyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-(pyrimidin-4-yl)-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid phenylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (4,5-dimethyl-thiazol-2-yl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-m-tolyl-ethyl)amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid pyridin-3-ylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (4-methyl-thiazol-2-ylmethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid-   (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-1-cyclohexyl-3-(3-phenyl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-2-hydroxy-2-phenyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((S)-2-hydroxy-2-phenyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid-   methyl-(2-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-hydroxy-1-methyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2,2-difluoro-1-methyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-fluoro-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid-   (3,3,3-trifluoro-1,1-dimethyl-propyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methanesulfonyl-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-fluoro-1-methyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-ethoxy-1-methyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3-methyl-tetrahydro-furan-3-yl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(5-methyl-[1,3,4]oxadiazol-2-yl)-ethyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(3,5-difluoro-pyridin-2-yl)-ethyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3,3-difluoro-1-methyl-cyclobutyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-1-cyclohexyl-3-(3-pyridin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1,2,2-trimethyl-propyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(R)-1-(5-fluoro-pyrimidin-2-yl)-ethyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid    [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide;-   5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide;-   5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclopentyl-piperidin-4-yl]-amide;-   5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclopropylmethyl-piperidin-4-yl]-amide;-   5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid    [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-(2-methyl-cyclopentyl)-piperidin-4-yl]-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)    H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid    ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)amide;-   (3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R*,2S1-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R*,2S1-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R*,2S1-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R*,2S1-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R*,2S1-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R*,    4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R*,    4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R*,2S1-2-phenyl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrazin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridazin-3-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrazin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridazin-3-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (cyano-dimethyl-methyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((3)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((3)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(S)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(3)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid (1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid (1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(1-oxy-pyridin-2-yl)-ethyl]-amide;-   (3R*,4R*)-1-(1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxymethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-ethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3,3-dimethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2,2-dimethyl-propyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3-methyl-butyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3,3-dimethyl-butyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-spiro[3.3]hept-2-yl-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(4-fluoro-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-(4,4-Difluoro-cyclohexyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3,3-dimethyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3-methoxy-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methoxy-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclobutylmethyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclopent-1-enylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Bicyclo[2.2.1]hept-2-yl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-(2-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-fluoro-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-(1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-spiro[2.4]hept-4-yl-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-ethyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyridin-2-yl-ethyl)-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid (1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methoxy-ethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1,1,2,2,2-d₅-ethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-cyclohexyl-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-4-{[5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-cyclohexyl-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (3-methoxy-1,1-dimethyl-propyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-cyclobutyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(5-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid benzylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-hydroxy-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid tert-butylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-methyl-cyclobutyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-methyl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (cyano-dimethyl-methyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-2-hydroxy-1-phenyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2H-pyrazol-3-yl)-ethyl]amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-3-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-4-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-4-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid-methyl-1-(1-methyl-1H-pyrazol-4-yl)-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid H-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid bicyclopropyl-1-ylamide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(tetrahydro-furan-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(1H-[1,2,4]triazol-3-yl)-ethyl]amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-prop-2-ynyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-isoxazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-methyl-1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid bicyclopropyl-1-ylamide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(tetrahydro-furan-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1H-[1,2,4]triazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-prop-2-ynyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-isoxazol-3-yl-ethyl)-amide;-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-3-methyl-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide; and-   (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-3-methyl-piperidine-3-carboxylic    acid dimethylamide;    22) In addition to the compounds of embodiment 21), further    compounds according to embodiment 1) are selected from the following    compounds:-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclobutyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-methoxy-phenyl)cyclopropyl]-amide;-   (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-cyano-cyclobutyl)-amide;-   (3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(1-Difluoromethyl-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(4-fluoro-benzyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2,2-dimethyl-propyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isobutyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ethyl-methyl-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methyl-(2-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methyl-(2-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-(2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3-fluoro-propyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Allyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Bicyclo[3.1.0]hex-3-yl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-propyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(3,3-Difluoro-cyclobutylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-spiro[2.3]hex-5-yl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(Cyclopropyl-(d₂-methyl))-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-phenyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-4-yl-cyclopropyl)-amide;-   1-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carbonyl)-amino]-cyclopropanecarboxylic    acid ethyl ester;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-phenyl-cyclobutyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid benzyl-(2-fluoro-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-methoxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-trifluoromethyl-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-fluoro-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-chloro-phenyl)-ethyl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-chloro-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(4-methyl-thiazol-2-yl)-cyclobutyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-methoxy-phenyl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-methoxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(3-bromo-phenyl)ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-hydroxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyrimidin-2-yl)-cyclopropyl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-(2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((S)-1-pyrimidin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3-benzyl-oxetan-3-yl)-amide;-   (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3-phenyl-oxetan-3-ylmethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [3-(3-chloro-phenyl)-oxetan-3-yl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(S)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1);-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dimethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[4-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide; and-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide.    23) Another embodiment relates to preferred compounds according to    embodiment 1) which are selected from the following compounds:-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ethylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ethylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (pyridin-2-ylmethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (pyridin-2-ylmethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [2-(2-oxo-pyrrolidin-1-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-oxo-pyrrolidin-1-yl)-ethyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (thiazol-2-ylmethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (thiazol-2-ylmethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-o-tolyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-o-tolyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [2-(2-methoxy-phenyl)-ethyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-methoxy-phenyl)-ethyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [2-(2-chloro-phenyl)-ethyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-chloro-phenyl)-ethyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid-   ((1R,2S)-2-phenyl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid-   ((1S,2R)-2-phenyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((1R,2S)-2-phenyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((1S,2R)-2-phenyl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-p-tolyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-p-tolyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-m-tolyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-m-tolyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-2-hydroxy-2-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-2-hydroxy-2-phenyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid-   methyl-(2-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   methyl-(2-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R)-2-ethoxy-1-methyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S)-2-ethoxy-1-methyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R)-2-ethoxy-1-methyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S)-2-ethoxy-1-methyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(R)-1-(5-fluoro-pyrimidin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(5-fluoro-pyrimidin-2-yl)-ethyl]-amide;-   (3R,4R)-1-((1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-((1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-((1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-((1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-((1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-((1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-((1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-((1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((R)-1-cyclobutyl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid-   ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((R)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid-   ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid-   (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-((1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-((1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-((1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-((1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-((1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-((1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-((1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-((1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]amino}-piperidine-3-carboxylic    acid-   (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid-   (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrazin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrazin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (cyano-dimethyl-methyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (cyano-dimethyl-methyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-((1R)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-14(1S)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-((1R)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-((1S)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic acid    dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic acid    dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylic acid    dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylic acid    dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1R)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1S)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1R)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1S)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid    dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid    dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylic acid    dimethylamide;-   (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-(2-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-(2-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-((1R)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-((1S)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid    methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid    methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic    acid methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S, 2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic acid    methyl-phenethyl-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1    S, 2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic acid    methyl-phenethyl-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1S)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((13)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((13)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((1R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid ((13)-1-pyridin-2-yl-ethyl)amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methoxy-ethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1,1,2,2,2-d₅-ethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid dimethylamide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R)-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((13)-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((3)-2-hydroxy-1-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid benzylamide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid [(1R)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid [(1S)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid ((R)-1-pyridin-3-yl-ethyl)amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-4-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid (1-pyridin-4-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1R)-1-isoxazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((1S)-1-isoxazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(1R)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(1S)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-3-yl-ethyl)-amide; and-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.    24) In addition to the compounds of embodiment 23), further    preferred compounds according to embodiment 1) are selected from the    following compounds:-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclobutyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclobutyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(2-methoxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-methoxy-phenyl)-cyclopropyl]-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-cyano-cyclobutyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-cyano-cyclobutyl)-amide;-   (3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(1-Difluoromethyl-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(4-fluoro-benzyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2,2-dimethyl-propyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isobutyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ethyl-methyl-amide;-   (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methyl-(2-pyridin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid methyl-(2-pyridin-2-yl-ethyl)amide;-   (3S,4S)-1-((1R)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-((1S)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3-fluoro-propyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Allyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Bicyclo[3.1.0]hex-3-yl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-propyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(3,3-Difluoro-cyclobutylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-spiro[2.3]hex-5-yl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(Cyclopropyl-(d₂-methyl))-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-phenyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-4-yl-cyclopropyl)-amide;-   1-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carbonyl)-amino]-cyclopropanecarboxylic    acid ethyl ester;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-phenyl-cyclobutyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid benzyl-(2-fluoro-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-methoxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-trifluoromethyl-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-fluoro-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-chloro-phenyl)-ethyl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-chloro-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(4-methyl-thiazol-2-yl)-cyclobutyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(2-methoxy-phenyl)-ethyl]-amide;-   (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(S)-1-(2-methoxy-phenyl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-methoxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(3-bromo-phenyl)ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-hydroxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyrimidin-2-yl)-cyclopropyl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]amide;-   5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrimidin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((S)-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((S)-1-pyrimidin-2-yl-ethyl)-amide;-   (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3-benzyl-oxetan-3-yl)-amide;-   (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (3-phenyl-oxetan-3-ylmethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [3-(3-chloro-phenyl)-oxetan-3-yl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(S)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3R,4R)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3R,4R)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1);-   (3S,4S)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1);-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dimethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[4-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide; and-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide.    25) Another embodiment relates to particularly preferred compounds    according to embodiment 1) which are selected from the following    compounds:-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyrazin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3S,4S)-1-Cyclopropyl    methyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-cyclobutyl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropyl    methyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3-carboxylic    acid (1-pyrazin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrazin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methoxy-ethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1,1,2,2,2-d₅-ethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropyl    methyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropyl    methyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (2-methoxy-1,1-dimethyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R)-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S)-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide;-   (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid benzylamide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(1R)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(1S)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-4-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-4-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1R)-1-isoxazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((1S)-1-isoxazol-3-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(1R)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [(1S)-1-(2H-pyrazol-3-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid ((R)-1-pyridin-3-yl-ethyl)-amide; and-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.    26) In addition to the compounds of embodiment 25), further    particularly preferred compounds according to embodiment 1) are    selected from the following compounds:-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(1-Difluoromethyl-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(4-fluoro-benzyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2,2-dimethyl-propyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isobutyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-((1R)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-((1S)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3-fluoro-propyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyridin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Allyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Bicyclo[3.1.0]hex-3-yl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-propyl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(3,3-Difluoro-cyclobutylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-spiro[2.3]hex-5-yl-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-(Cyclopropyl-(d₂-methyl))-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-phenyl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-4-yl-cyclopropyl)-amide;-   1-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carbonyl)-amino]-cyclopropanecarboxylic    acid ethyl ester;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-phenyl-cyclobutyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid benzyl-(2-fluoro-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-methoxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-trifluoromethyl-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-fluoro-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [2-(2-chloro-phenyl)-ethyl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-chloro-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(4-methyl-thiazol-2-yl)-cyclobutyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(2-methoxy-phenyl)-ethyl]-amide;-   (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(S)-1-(2-methoxy-phenyl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-methoxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(3-bromo-phenyl)ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(2-hydroxy-phenyl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(1-oxy-pyrimidin-2-yl)-cyclopropyl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid    [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrimidin-2-yl-ethyl)amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((S)-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((R)-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid ((S)-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [3-(3-chloro-phenyl)-oxetan-3-yl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid [(S)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dimethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[4-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide;-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide; and-   (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic    acid (1-pyrimidin-2-yl-cyclopropyl)-amide.    27) A further aspect of the invention relates to novel piperidine    derivatives of formula (II);

whereinthe two substituents of the piperidine ring: R¹—CO— and —NH—CO—Ar¹—Ar²,are in relative trans-configuration (i.e. the relative configuration ofthe two chiral carbon atoms in position 3 and 4 of the piperidine ringis (3R*,4R*));Ar¹ represents a 5-membered heteroarylene group (especially a 5-memberedheteroarylene containing one to a maximum of three heteroatoms, eachindependently selected from oxygen and nitrogen; notably oxazol-diyl,isoxazol-diyl, oxadiazol-diyl, or triazol-diyl), wherein the —NH—CO—group and Ar² are attached in meta arrangement to ring atoms of Art;wherein said 5-membered heteroarylene is unsubstituted, ormono-substituted with R^(Ar1); wherein R^(Ar1) represents (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy(especially said 5-membered heteroarylene is unsubstituted);Ar² represents phenyl which is mono-, di- or tri-substituted, whereinthe substituents are independently fluoro or chloro (especially Ar²represents phenyl which is mono-, di- or tri-substituted with fluoro);R⁵ represents (C₁₋₆)alkyl;R² represents

-   -   hydrogen;    -   (C₁₋₆)alkyl (especially ethyl, isopropyl, 2,2-dimethylpropyl,        3-methyl-butyl, 3,3-dimethylbutyl);    -   (C₂₋₆)alkyl which is mono-substituted with (C₁₋₃)alkoxy        (especially methoxy), or hydroxy (especially 2-hydroxyethyl,        2-methoxy-ethyl, 2-hydroxy-1-methyl-propyl);    -   (C₂₋₃)fluoroalkyl;    -   (C₃₋₈)cycloalkyl-(C₀₋₃)alkyl; wherein said (C₃₋₈)cycloalkyl        group may optionally contain one ring oxygen atom; wherein the        (C₃₋₈)cycloalkyl is unsubstituted, or mono- or di-substituted        wherein the substituents are independently selected from        (C₁₋₃)alkyl (especially methyl), fluoro, hydroxy,        hydroxy-(C₁₋₃)alkyl (especially hydroxy-methyl), or (C₁₋₃)alkoxy        (especially methoxy);    -   (especially cyclobutyl, 2-methylcyclobutyl,        2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl,        cyclohexyl, spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl,        bicyclo[2.2.1]hept-2-yl, 2-methylcyclopentyl,        2-(hydroxymethyl)-cyclopentyl, 3,3-dimethylcyclopentyl,        2-ethylcyclopentyl, 3,3-dimethylcyclohexyl, 2-fluoro-cyclohexyl,        4-fluoro-cyclohexyl, 4,4-difluoro-cyclohexyl,        2-hydroxy-cyclohexyl, 2-methoxy-cyclohexyl,        3-methoxy-cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,        cyclopentylmethyl, 1-cyclopropyl-ethyl,        (1-methyl-cyclopropyl)-methyl, (1-methyl-cyclobutyl)-methyl,        2-cyclopropyl-ethyl); or    -   (C₃₋₈)cycloalkenyl-(C₁₋₃)alkyl (especially        cyclopenten-1-yl-methyl); and        R³ represents hydrogen, or methyl (especially hydrogen).

The compounds of formula (II) are important intermediates suitable forthe preparation of the compounds of formula (I) as described in reactionscheme A below. In addition, such compounds of formula (II) may also actas CXCR7 receptor antagonists, and may, thus, be useful for theprevention or treatment of diseases which respond to the activation ofthe CXCL12 receptors and/or CXCL11 receptors, especially cancer.

It is understood that the characteristics of embodiments 2) to 10) and15) to 19), especially as set out in embodiment 20), apply mutatismutandis also to the compounds of formula (II).

The compounds of formula (I) according to embodiments 1) to 26) andtheir pharmaceutically acceptable salts can be used as medicaments, e.g.in the form of pharmaceutical compositions for enteral (such especiallyoral) or parenteral administration (including topical application orinhalation).

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the described compounds of formula (I)or (II), or their pharmaceutically acceptable salts, optionally incombination with other therapeutically valuable substances, into agalenical administration form together with suitable, non-toxic, inert,therapeutically compatible solid or liquid carrier materials and, ifdesired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention ortreatment of a disease or disorder mentioned herein comprisingadministering to a subject a pharmaceutically active amount of acompound of formula (I) as defined in any one of embodiments 1) to 26).

In a preferred embodiment of the invention, the administered amount iscomprised between 1 mg and 1000 mg per day, particularly between 5 mgand 500 mg per day, more particularly between 25 mg and 400 mg per day,especially between 50 mg and 200 mg per day.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.

For avoidance of any doubt, if compounds are described as useful for theprevention or treatment of certain diseases, such compounds are likewisesuitable for use in the preparation of a medicament for the preventionor treatment of said diseases.

The compounds of formula (I) as defined in any one of embodiments 1) to26) are useful for the prevention/prophylaxis or treatment of disordersrelating to the CXCR7 receptor or its ligands which are especially todisorders relating to a dysfunction of the CXCR7 receptor, ordysfunction of ligands signalling through CXCR7, or dysfunction of CXCR7ligands (CXCL12 and CXCL11) signalling through their other receptors(CXCR4 and CXCR3).

Diseases or disorders relating to the CXCR7 receptor or its ligands areespecially selected from the group consisting of

-   -   cancer (notably brain tumors including malignant gliomas,        glioblastoma multiforme; neuroblastoma; pancreatic cancer        including pancreatic adenocarcinoma/pancreatic ductal        adenocarcinoma; gastro-intestinal cancers including colon        carcinoma, hepatocellular carcinoma; Kaposi's sarcoma; leukemias        including adult T-cell leukemia; lymphoma; lung cancer; breast        cancer; rhabdomyosarcoma; prostate cancer; esophageal squamous        cancer; oral squamous cell carcinoma; endometrial cancer;        thyroid carcinoma including papillary thyroid carcinoma;        metastatic cancers; lung metastasis; skin cancer including        melanoma and metastatic melanoma; bladder cancer; multiple        myelomas; osteosarcoma; head and neck cancer; and renal        carcinomas including renal clear cell carcinoma, metastatic        renal clear cell carcinoma);    -   inflammatory diseases (notably chronic rhinosinusitis, asthma,        chronic obstructive pulmonary disorder, atherosclerosis,        myocarditis, and sarcoidosis; especially chronic rhinosinusitis,        asthma, and atherosclerosis);    -   autoimmune disorders (notably (inflammatory) demyelinating        diseases; multiple sclerosis (MS); Guillain Barr syndrome;        rheumatoid arthritis (RA); inflammatory bowel diseases (IBD,        especially comprising Crohn's disease and ulcerative colitis);        systemic lupus erythematosus (SLE); lupus nephritis;        interstitial cystitis; celiac disease; autoimmune        encephalomyelitis; osteoarthritis; and type I diabetes;        especially autoimmune disorders which have an inflammatory        component such as (inflammatory) demyelinating diseases,        multiple sclerosis, Guillain Barr syndrome, rheumatoid        arthritis, inflammatory bowel diseases, systemic lupus        erythematosus, lupus nephritis, and auto-immune        encephalomyelitis);    -   transplant rejection (notably renal allograft rejection, cardiac        allograft rejection, and graft-versus-host diseases brought        about by hematopoietic stem cell transplantation); and    -   fibrosis (notably liver fibrosis, liver cirrhosis, lung        fibrosis, especially idiopathic pulmonary fibrosis).

Notably such diseases or disorders relating to the CXCR7 receptor or itsligands are cancers, autoimmune disorders (especially autoimmunedisorders which have an inflammatory component), and fibrosis.

In addition, further diseases or disorders relating to the CXCR7receptor or its ligands are diseases involving CXCR7 and/or CXCL12and/or CXCL11 mediated metastasis, chemotaxis, cell adhesion,trans-endothelial migration, cell proliferation and/or survival.

In addition, further particular diseases or disorders relating to theCXCR7 receptor or its ligands are proliferative diabetic retinopathy;West Nile virus encephalitis; pulmonary vascular diseases, acute renalfailure, ischemia including cerebral ischemia, acute coronary syndrome,injured central nervous system, hypertension, pulmonary hypertension,Shiga-toxin-associated heomolytic uremic syndrome, preeclampsia,vascular injury, HIV/AIDS, angiogenesis, and brain and neuronaldysfunctions (such as inflammatory components of Alzheimer's disease),stress-related disorders (such as anxiety, depression, and posttraumaticstress disorder), and diseases involving opioid receptors. In asub-embodiment, such a further particular disease or disorder relatingto the CXCR7 receptor or its ligands is especially pulmonaryhypertension.

The term “cancer” refers to all sorts of cancers such as carcinomas;adenocarcinomas; leukemias; sarcomas; lymphomas; myelomas; metastaticcancers; brain tumors; neuroblastomas; pancreatic cancers;gastro-intestinal cancers; lung cancers; breast cancers; prostatecancers; endometrial cancers; skin cancers; bladder cancers; head andneck cancers; neuroendocrine tumors; ovarian cancers; cervical cancers;oral tumors; nasopharyngeal tumors; thoracic cancers; and virallyinduced tumors.

Notably the term refers to brain tumors including brain metastases,malignant gliomas, glioblastoma multiforme, medulloblastoma,meningiomas; neuroblastoma; pancreatic cancer including pancreaticadenocarcinoma/pancreatic ductal adenocarcinoma; gastro-intestinalcancers including colon carcinoma, colorectal adenoma, colorectaladenocarcinoma, metastatic colorectal cancer, familial adenomatouspolyposis (FAP), gastric cancer, gallbladder cancer, cholangiocarcinoma,hepatocellular carcinoma; Kaposi's sarcoma; leukemias including acutemyeloid leukemia, adult T-cell leukemia; lymphomas including Burkitt'slymphoma, Hodgkin's lymphoma, MALT lymphoma, and primary intra-ocularB-Cell lymphoma; lung cancer including non-small cell lung cancer;breast cancer including triple negative breast carcinoma;rhabdomyosarcoma; prostate cancer including castrate-resistant prostatecancer; esophageal squamous cancer; (oral) squamous cell carcinoma;endometrial cancer; thyroid carcinoma including papillary thyroidcarcinoma; metastatic cancers; lung metastasis; skin cancer includingmelanoma and metastatic melanoma; bladder cancer including urinarybladder cancer, urothelial cell carcinoma; multiple myelomas;osteosarcoma; head and neck cancer; and renal carcinomas including renalcell carcinoma renal clear cell carcinoma, metastatic renal cellcarcinoma, metastatic renal clear cell carcinoma; as well asneuroendocrine tumors; ovarian cancer; cervical cancer; oral tumors;nasopharyngeal tumors; thoracic cancer; choriocarcinoma; Ewing'ssarcoma; and virally induced tumors.

Especially the term “cancer” refers to malignant glioma in particularglioblastoma multiforme, neuroblastoma; pancreatic cancers in particularpancreatic ductal adenocarcinoma; Kaposi's sarcoma; adult T-cellleukemia, lymphoma; lung cancer; breast cancer; rhabdomyosarcoma;prostate cancer; esophageal squamous cancer; (oral) squamous cellcarcinoma; endometrial cancer; papillary thyroid carcinoma; metastaticcancer; lung metastasis; melanoma; bladder cancer; multiple myelomas;osteosarcoma; gastro-intestinal cancers, in particular colon carcinoma,hepatocellular carcinoma; head and neck cancer; and renal clear cellcarcinoma. Preferably the term “cancer” refers to malignant glioma, inparticular glioblastoma multiforme; pancreatic cancers, in particularpancreatic ductal adenocarcinoma; papillary thyroid carcinoma;hepatocellular carcinoma; lung cancer; breast cancer; metastaticcancers; lung metastasis; melanoma; colon carcinoma; and head and neckcancer.

The compounds of formula (I) as defined in any one of embodiments 1) to26) may in particular be useful as therapeutic agents for theprevention/prophylaxis or treatment of a cancer as defined before, whichcancer is a metastatic cancer/a cancer which forms metastasis.

The compounds of formula (I) as defined in any one of embodiments 1) to26) are in particular useful as therapeutic agents for theprevention/prophylaxis or treatment of a cancer. They can be used assingle therapeutic agents or in combination with one or morechemotherapy agents and/or radiotherapy and/or targeted therapy. In asub-embodiment, when a compound of formula (I) is used for theprevention/prophylaxis or treatment of a cancer in combination with oneor more chemotherapy agents and/or radiotherapy and/or targeted therapy,such cancer is especially a malignant glioma, in particular aglioblastoma multiforme; pancreatic cancer, especially pancreatic ductaladenocarcinoma; papillary thyroid carcinoma; lung metastasis; melanoma;lung cancer; metastatic cancers; hepatocellular carcinoma; breastcancer; colorectal cancer; or head and neck cancer. Such combinedtreatment may be effected simultaneously, separately, or over a periodof time.

The invention, thus, also relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier material, and:

-   -   a compound of formula (I) as defined in any one of        embodiments 1) to 26);    -   and one or more cytotoxic chemotherapy agents.

The invention, thus, further relates to a kit comprising

-   -   a pharmaceutical composition, said composition comprising a        pharmaceutically acceptable carrier material, and a compound of        formula (I) as defined in any one of embodiments 1) to 26);    -   and instructions how to use said pharmaceutical composition for        the prevention or the treatment of a cancer (especially of a        malignant glioma, in particular of a glioblastoma multiforme),        in combination with chemotherapy and/or radiotherapy and/or        targeted therapy.

The terms “radiotherapy” or “radiation therapy” or “radiation oncology”,refer to the medical use of ionizing radiation in the prevention(adjuvant therapy) and/or treatment of cancer; including external andinternal radiotherapy.

The term “targeted therapy” refers to the prevention/prophylaxis(adjuvant therapy) and/or treatment of cancer with one or moreanti-neoplastic agents such as small molecules or antibodies which acton specific types of cancer cells or stromal cells. Some targetedtherapies block the action of certain enzymes, proteins, or othermolecules involved in the growth and spread of cancer cells. Other typesof targeted therapies help the immune system kill cancer cells(immunotherapies); or deliver toxic substances directly to cancer cellsand kill them. An example of a targeted therapy which is in particularsuitable to be combined with the compounds of the present invention isimmunotherapy, especially immunotherapy targeting the progammed celldeath receptor 1 (PD-1 receptor) or its ligand PD-L1 (Feig C et al, PNAS2013).

When used in combination with the compounds of formula (I), the term“targeted therapy” especially refers to agents such as:

a) Epidermal growth factor receptor (EGFR) inhibitors or blockingantibodies (for example Gefitinib, Erlotinib, Afatinib, Icotinib,Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab, Matuzumab andCetuximab);b) B-RAF inhibitors (for example Vemurafenib, Sorafenib,Dabrafenib,GDC-0879, PLX-4720, LGX818);c) Aromatase inhibitors (for example Exemestane, Letrozole, Anastrozole,Vorozole, Formestane, Fadrozole);d) Immune Checkpoint inhibitors (for example, anti-PD1 antibodies suchas Pembrolizumab (Lambrolizumab, MK-3475), Nivolumab, Pidilizumab,AMP-514/MED10680; small molecule anti PD1 agents such as for examplecompounds disclosed in WO2015/033299, WO2015/044900 and WO2015/034820;anti-PD1L antibodies, such as BMS-936559, atezolizumab (MPDL3280A),MED14736, avelumab (MSB0010718C); anti-PDL2, such as AMP224, anti-CTLA-4antibodies, such as ipilimumab, tremilmumab);e) Vaccination approaches (for example dendritic cell vaccination,peptide or protein vaccination (for example with gp100 peptide orMAGE-A3 peptide);f) Re-introduction of patient derived or allogenic (non-self) cancercells genetically modified to secrete immunomodulatory factors such asgranulocyte monocyte colony stimulating factor (GMCSF) gene-transfectedtumor cell vaccine (GVAX) or Fms-related tyrosine kinase 3 (Flt-3)ligand gene-transfected tumor cell vaccine (FVAX), or Toll like receptorenhanced GM-CSF tumor based vaccine (TEGVAX);g) T-cell based adoptive immunotherapies, including chimeric antigenreceptor (CAR) engineered T-cells (for example CTL019);h) Cytokine or immunocytokine based therapy (for example Interferonalpha, interferon beta, interferon gamma, interleukin 2, interleukin15);i) Toll-like receptor (TLR) agonists (for example resiquimod, imiquimod,glucopyranosyl lipid A, CpG oligodesoxynucleotides);j) Thalidomide analogues (for example Lenalidomide, Pomalidomide);k) Indoleamin-2,3-Dioxgenase (IDO) and/or Tryptophane-2,3-Dioxygenase(TDO) inhibitors (for example NLG919/Indoximod, 1MT(1-methyltryptophan), INCB024360);l) Activators of T-cell co-stimulatory receptors (for exampleanti-Lymphocyte-activation gene 3 (LAG-3) antibodies (such asBMS-986016); anti T cell immunoglobulin mucin-3 (TIM-3) antibodies,anti-CD137/4-1BB antibodies (for example BMS-663513/urelumab),anti-Killer-cell immunoglobulin-like receptors (KIR) for exampleLirilumab (IPH2102/BMS-986015); anti-OX40/CD134 (Tumor necrosis factorreceptor superfamily, member 4), anti OX40-Ligand/CD252;anti-glucocorticoid-induced TNFR family related gene (GITR) (such asTRX518), anti-CD40 (TNF receptor superfamily member 5) antibodies (suchas CP-870,893); anti-CD40-Ligand antibodies (such as BG9588); anti-CD28antibodies);m) Molecules binding a tumor specific antigen as well as a T-cellsurface marker such as bispecific antibodies or antibody fragments,antibody mimetic proteins such as designed ankyrin repeat proteins(DARPINS), bispecific T-cell engager (BITE, for example AMG103, AMG330);n) Antibodies or small molecular weight inhibitors targetingcolony-stimulating factor-1 receptor (CSF-1R) (for example RG7155 orPLX3397).

When used in combination with the compounds of formula (I), immunecheckpoint inhibitors such as those listed under d), and especiallythose targeting the progammed cell death receptor 1 (PD-1 receptor) orits ligand PD-L1, are preferred.

The term “chemotherapy” refers to the treatment of cancer with one ormore cytotoxic anti-neoplastic agents (“cytotoxic chemotherapy agents”).Chemotherapy is often used in conjunction with other cancer treatments,such as radiation therapy or surgery. The term especially refers toconventional chemotherapeutic agents which act by killing cells thatdivide rapidly, one of the main properties of most cancer cells.Chemotherapy may use one drug at a time (single-agent chemotherapy) orseveral drugs at once (combination chemotherapy or polychemotherapy).Chemotherapy using drugs that convert to cytotoxic activity only uponlight exposure is called photochemotherapy or photodynamic therapy.

The term “cytotoxic chemotherapy agent” or “chemotherapy agent” as usedherein refers to an active anti-neoplastic agent inducing apoptosis ornecrotic cell death. When used in combination with the compounds offormula (I), the term especially refers to conventional cytotoxicchemotherapy agents such as:

-   a) alkylating agents (for example mechlorethamine, chlorambucil,    cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine,    melphalan, busulfan, dacarbazine, temozolomide, thiotepa or    altretamine; in particular temozolomide);-   b) platinum drugs (for example cisplatin, carboplatin or    oxaliplatin);-   c) antimetabolite drugs (for example 5-fluorouracil, capecitabine,    6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine    or pemetrexed);-   d) anti-tumor antibiotics (for example daunorubicin, doxorubicin,    epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or    mitoxantrone);-   e) mitotic inhibitors (for example paclitaxel, docetaxel,    ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or    estramustine); or-   f) topoisomerase inhibitors (for example etoposide, teniposide,    topotecan, irinotecan, diflomotecan or elomotecan).

When used in combination with the compounds of formula (I), preferredcytotoxic chemotherapy agents are the above-mentioned alkylating agents(notably mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide,streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine,3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and prodrugsthereof such as especially temozolomide, thiotepa, altretamine; orpharmaceutically acceptable salts of these compounds; in particulartemozolomide); and mitotic inhibitors (notably paclitaxel, docetaxel,ixabepilone, vinblastine, vincristine, vinorelbine, vindesine,estramustine; or pharmaceutically acceptable salts of these compounds;in particular paclitaxel). Most preferred cytotoxic chemotherapy agentsto be used in combination with the compounds of formula (I) are thoseroutinely used in the treatment of glioblastoma multiforme, inparticular temozolomide. Equally preferred is radiotherapy.

Chemotherapy may be given with a curative intent or it may aim toprolong life or to palliate symptoms.

-   a) Combined modality chemotherapy is the use of drugs with other    cancer treatments, such as radiation therapy or surgery.-   b) Induction chemotherapy is the first line treatment of cancer with    a chemotherapeutic drug. This type of chemotherapy is used for    curative intent.-   c) Consolidation chemotherapy is the given after remission in order    to prolong the overall disease free time and improve overall    survival. The drug that is administered is the same as the drug that    achieved remission.-   d) Intensification chemotherapy is identical to consolidation    chemotherapy but a different drug than the induction chemotherapy is    used.-   e) Combination chemotherapy involves treating a patient with a    number of different drugs simultaneously. The drugs differ in their    mechanism and side effects. The biggest advantage is minimising the    chances of resistance developing to any one agent. Also, the drugs    can often be used at lower doses, reducing toxicity.-   f) Neoadjuvant chemotherapy is given prior to a local treatment such    as surgery, and is designed to shrink the primary tumor. It is also    given to cancers with a high risk of micrometastatic disease.-   g) Adjuvant chemotherapy is given after a local treatment    (radiotherapy or surgery). It can be used when there is little    evidence of cancer present, but there is risk of recurrence. It is    also useful in killing any cancerous cells that have spread to other    parts of the body. These micrometastases can be treated with    adjuvant chemotherapy and can reduce relapse rates caused by these    disseminated cells.-   h) Maintenance chemotherapy is a repeated low-dose treatment to    prolong remission.-   i) Salvage chemotherapy or palliative chemotherapy is given without    curative intent, but simply to decrease tumor load and increase life    expectancy. For these regimens, a better toxicity profile is    generally expected.

When combined with the compounds of formula (I), preventive or curativeforms of chemotherapy (or mutatis mutandis: radiotherapy) such as thoselisted under a), b) c), d), e), and especially g) and/or h) above arepreferred.

“Simultaneously”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat approximately the same time; wherein it is understood that asimultaneous administration will lead to exposure of the subject to thetwo or more active ingredients and/or treatments at the same time. Whenadministered simultaneously, said two or more active ingredients may beadministered in a fixed dose combination, or in an equivalent non-fixeddose combination (e.g. by using two or more different pharmaceuticalcompositions to be administered by the same route of administration atapproximately the same time), or by a non-fixed dose combination usingtwo or more different routes of administration; wherein saidadministration leads to essentially simultaneous exposure of the subjectto the two or more active ingredients and/or treatments.

“Fixed dose combination”, when referring to an administration type,means in the present application that the administration type concernedconsists in the administration of one single pharmaceutical compositioncomprising the two or more active ingredients.

“Separately”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat different points in time; wherein it is understood that a separateadministration will lead to a treatment phase (e.g. at least 1 hour,notably at least 6 hours, especially at least 12 hours) where thesubject is exposed to the two or more active ingredients and/ortreatments at the same time; wherein such “separate administration” mayunder certain circumstances also encompass a treatment phase where for acertain period of time (e.g. at least 12 hours, especially at least oneday) the subject is exposed to only one of the two or more activeingredients and/or treatments. Separate administration thus especiallyrefers to situations wherein one active ingredient and/or treatment isgiven e.g. once a day, and another is given e.g. twice a day, thrice aday, every other day, wherein as a consequence of such administrationtype the subject is exposed to the two or more active ingredients and/ortreatments the same time during essentially the whole treatment period.Separate administration also refers to situations wherein at least oneof the active ingredients and/or treatments is given with a periodicitysubstantially longer than daily (such as once or twice daily)administration (e.g. wherein one active ingredient and/or treatment isgiven e.g. once or twice a day, and another is given once a week). Forexample when used in combination with (e.g. weekly or bi-weekly)radiotherapy the present CXCR7 modulators would possibly be used“separately”.

By administration “over a period of time” is meant in the presentapplication the subsequent administration of two or more activeingredients and/or treatments at different times. The term in particularrefers to an administration method according to which the entireadministration of one of the active ingredients and/or treatments iscompleted before the administration of the other/the others begins. Inthis way it is possible to administer one of the active ingredientsand/or treatments for several months before administering the otheractive ingredient(s) and/or treatment(s).

Administration “over a period of time” also encompasses situationswherein the CXCR7 modulators of formula (I) or (II) would be used in atreatment that starts after termination of an initial chemotherapeuticor radiotherapeutic treatment or targeted therapy (for example aninduction chemotherapy), wherein optionally said treatment would be incombination with a further/an ongoing chemotherapeutic orradiotherapeutic treatment or targeted therapy treatment (for example incombination with a consolidation chemotherapy, an intensificationchemotherapy, an adjuvant chemotherapy, or a maintenance chemotherapy;or radiotherapeutic equivalents thereof); wherein such further/ongoingchemotherapeutic or radiotherapeutic treatment or targeted therapy wouldbe simultaneously or separately with the treatment using the CXCR7modulator.

Autoimmune disorders may be defined as comprising (inflammatory)demyelinating diseases; multiple sclerosis (MS); Guillain Barr syndrome;rheumatoid arthritis (RA); inflammatory bowel disease (IBD, especiallycomprising Crohn's disease and ulcerative colitis); systemic lupuserythematosus (SLE); lupus nephritis; interstitial cystitis; celiacdisease; autoimmune encephalomyelitis; osteoarthritis; and type Idiabetes. In addition, autoimmune diseases further comprise disorderssuch as psoriasis; psoriatic arthritis; antiphospholipid syndrome;thyroiditis such as Hashimoto's thyroiditis; lymphocytic thyroiditis;myasthenia gravis; uveitis; episcleritis; scleritis; Kawasaki's disease;uveo-retinitis; posterior uveitis; uveitis associated with Behcet'sdisease; uveomeningitis syndrome; allergic encephalomyelitis; atopicdiseases such as rhinitis, conjunctivitis, dermatitis; andpost-infectious autoimmune diseases including rheumatic fever andpost-infectious glomerulonephritis. In a sub-embodiment, autoimmunedisorders especially refer to autoimmune disorders which have aninflammatory component wherein particular examples are (inflammatory)demyelinating diseases, multiple sclerosis (MS), Guillain Barr syndrome,rheumatoid arthritis (RA), inflammatory bowel disease (IBD, especiallycomprising Crohn's disease and ulcerative colitis), systemic lupuserythematosus (SLE), lupus nephritis, and auto-immune encephalomyelitis.

Inflammatory diseases may be defined as comprising especially chronicrhinusitis, as well as asthma, chronic obstructive pulmonary disorder(COPD), atherosclerosis, myocarditis, dry eye disease, sarcoidosis,inflammatory myopathies, and acute lung injury.

Transplant rejection may be defined as comprising rejection oftransplanted organs such as kidney, liver, heart, lung, pancreas,cornea, and skin; graft-versus-host diseases brought about byhematopoietic stem cell transplantation; chronic allograft rejection andchronic allograft vasculopathy.

Fibrosis may be defined as comprising especially liver fibrosis, livercirrhosis, lung fibrosis, idiopathic pulmonary fibrosis, renal fibrosis,endomyocardial fibrosis, and arthrofibrosis.

The compounds of formula (I) according to embodiments 1) to 31) are alsouseful in method of prophylaxis or treating tumors comprisingadministering an effective amount of the compound of formula (I) whereinsaid effective amount leads to a change of tumor properties, and whereinsaid modification is achieved by modulating the CXCL11/CXCL12 receptorpathway; wherein said prophylaxis or treatment may optionally beeffected in combination with a conventional chemotherapeutic orradiotherapeutic treatment (in which case the tumor is notably amalignant glioma, in particular a glioblastoma multiforme). Suchcombined treatment may be effected simultaneously, separately, and/orover a period of time.

The compounds of formula (I) are also useful in method of modulating animmune response comprising the administration of an effective amount ofthe compound of formula (I) wherein said effective amount modulates aninflammatory disease and wherein said response is mediated by theCXCL11/CXCL12 receptor pathway.

Preparation of Compounds of Formula (I)

The compounds of formula (I) can be prepared by the methods given below,by the methods given in the experimental part below or by analogousmethods. Optimum reaction conditions may vary with the particularreactants or solvents used, but such conditions can be determined by aperson skilled in the art by routine optimisation procedures. In theschemes below, the generic groups Ar¹, Ar², R¹, R², R³, R^(Ar1), R^(N1),R^(N2) are as defined for the compounds of formula (I). In someinstances the generic groups Ar¹, Ar², R¹, R², R³, R^(Ar1), R^(N1),R^(N2) may be incompatible with the assembly illustrated in the schemes,or will require the use of protecting groups (PG). The use of protectinggroups is well known in the art (see for example “Protective Groups inOrganic Synthesis”, T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999).For the purposes of this discussion, it will be assumed that suchprotecting groups as necessary are in place. In some cases the finalproduct may be further modified, for example, by manipulation ofsubstituents to give a new final product. These manipulations mayinclude, but are not limited to, reduction, oxidation, alkylation,acylation, and hydrolysis reactions which are commonly known to thoseskilled in the art. The compounds obtained may also be converted intosalts, especially pharmaceutically acceptable salts in a manner knownper se.

Compounds of formula (I) of the present invention can be preparedaccording to the general sequence of reactions outlined below.

Compounds of formula (I) are prepared by reaction of an acid ofStructure 1 (L¹=OH), or a salt such as a sodium or lithium salt thereof,with an amine of Structure 2 in the presence of an amide-couplingreagent such as TBTU, HATU, COMU, EDC, DCC, T₃P or PyBOP and a base likeDIPEA or TEA in a solvent such as DCM, MeCN or DMF.

Compounds of Structure 1 may be prepared by one of the syntheticpathways described below.

Compounds of Structure 1 may be prepared by the procedure illustrated inReaction Scheme A. A commercially available alkyl(3R*,4R*)-4-((tert-butoxycarbonyl)amino)piperidine-3-carboxylate A-1(R⁵=alkyl) is N-alkylated by treatment with an aldehyde or a ketone inthe presence of a reductive reagent like NaBH₄, NaBH₃CN, NaBH(OAc)₃ in asolvent like DCM, MeOH, THF; or in the presence of a titanium salt likeTiCl₄ or tetraisopropyl-orthotitanate, to give the tertiary amine A-2.The intermediate A-2 is Boc-deprotected by treatment with an acid,preferentially 4M HCl in dioxane or TFA in DCM, to give thecorresponding amine A-3. The amine A-3 can be acylated by reaction withan acid A-4 in the presence of an amide-coupling reagent such as TBTU,HATU, COMU, EDC, DCC, T₃P or PyBOP and a base like DIPEA or TEA in asolvent such as DCM, MeCN or DMF. Hydrolysis of the ester A-5 bytreatment with a base like NaOH or LiOH in a solvent like methanol,ethanol or water/THF at temperature between RT and 60° C. gives thecorresponding acid of Structure 1.

Compounds of formula (I) may alternatively be prepared as illustrated inReaction Scheme B. Amidation of the commercially available alkyl(3R*,4R*)-4-amino-1-benzylpiperidine-3-carboxylate B-1 with an acid ofStructure A-4 (L¹=OH) in the presence of an amide-coupling reagent suchas TBTU, HATU, COMU, EDC, DCC, T₃P or PyBOP and a base like DIPEA or TEAin a solvent such as DCM, MeCN or DMF; or the corresponding acylchloride (L¹=Cl) and a base like DIPEA or TEA in a solvent like DCMgives the corresponding amide B-2. The N-benzyl protective group isremoved by catalytic hydrogenation in the presence of Pd on charcoal ina solvent like AcOEt preferably at atmospheric pressure of hydrogen, inthe presence of di-tert-butyl dicarbonate in order to obtain theBoc-N-protected derivative B-3. Hydrolysis of the ester group of B-3 bytreatment with a base like NaOH or LiOH in a solvent like methanol,ethanol or water/THF at temperature between RT and 60° C. gives thecorresponding acid B-4. 3-Piperidine carboxamides of type B-5 areobtained by amidation of B-4 with an amine of Structure 2 in thepresence of an amide-coupling reagent such as TBTU, HATU, COMU, EDC,DCC, T₃P or PyBOP and a base like DIPEA or TEA in a solvent such as DCM,MeCN or DMF. The carbamate B-5 is Boc-deprotected as described before togive the piperidine B-6. N-alkylation of B-6 by treatment with analdehyde or a ketone in the presence of a reductive reagent like NaBH₄,NaBH₃CN, NaBH(OAc)₃ in a solvent like DCM, MeOH, THF, DMF; and in thecase of R^(3a)=alkyl, in the presence of a titanium salt like TiCl₄ ortetraisopropyl-orthotitanate, to give compounds of formula (I).Alternatively compounds of formula (I) can be prepared by alkylation ofintermediate B-6 with an alkyl halogenide or alkyl sulfonate in thepresence of a base like DIPEA, TEA, or K₂CO₃ in a solvent like DMF, MeCNor EtOH. In the case where R² represents (C₁₋₆)alkyl or a(C₃₋₈)cycloalkyl which is mono-substituted with an hydroxyl group,compounds of formula (I) can be obtained by condensation of an amine ofStructure B-6 and a mono or disubstituted epoxide in a polar aproticsolvent like MeCN in the presence of calcium trifluoromethanesulfonateat RT or in water at temperature between RT and refluxing temperature.

Compounds of formula (I) may alternatively be prepared as illustrated inReaction Scheme C. A commercially available alkyl(3R*,4R*)-4-((tert-butoxycarbonyl)amino)piperidine-3-carboxylate A-1(R⁵=alkyl) is N-alkylated by treatment with an aldehyde or a ketone asdescribed for B-6 before to give the tertiary amine A-2. TheN-substituted alkyl(3R*,4R*)-4-((tert-butoxycarbonyl)amino)piperidine-3-carboxylate A-2 canbe hydrolysed to the acid C-1 by treatment with a base like NaOH or LiOHin a solvent like methanol, ethanol or a mixture water/THF attemperature between RT and 60° C. Piperidinyl carboxamide C-2 areprepared by condensation of an amine of Structure 2 in the presence ofan amide-coupling reagent such as TBTU, HATU, COMU, EDC, DCC, T₃P orPyBOP and a base like DIPEA or TEA in a solvent such as DCM, MeCN orDMF. The intermediate C-2 is Boc-deprotected as described before to givethe corresponding amine C-3. Acylation of 4-amino-3-carboxamide C-3 maybe achieved by treatment of the in situ prepared 4-dimethylaluminumamide resulting from the reaction of a trialkyl aluminium compound liketrimethyl aluminium with C-3 in a solvent like toluene, DCM or DCE attemperatures between RT and reflux followed by condensation with anester or a carboxylic acid A-4 (L1=O-alkyl or OH) to give compound offormula (I).

For the synthesis of [S,S] 3,4-disubstitued piperidines the sequenceshown in Scheme D can be used, following the procedure described by S.Gellman et al. Eur. J. Org. Chem. 2003, 721. The enamine D-2 of theN-Boc protected 4-ketopiperidine D-1 can be prepared by heating with(S)-(−)-α-methyl benzylamine in toluene in presence of a catalyticamount of an acid, like p-toluensulfonic acid with Dean-Stark trapping.Reduction of the enamine D-2 with a reducing agent like sodiumtriisobutyroxyborohydride, sodium trifluroacetoxyborohydride or withsodium triacetoxyborohydride in toluene, THF or dioxane at temperaturesbetween −78° C. and RT gives predominantly the cis-amino ester D-3.Epimerization to the trans-amino ester D-4 can be done by treatment witha base like sodium ethoxyde, sodium methoxyde or potassium t-butoxyde ina solvent like EtOH, MeOH, t-BuOH in the presence of ethylacetate,methylacetate or t-butylacetate at temperature between 0° C. and reflux.Hydrogenolysis of the benzyl group by catalytic hydrogenation in thepresence of Pd on charcoal or Pd hydroxide in a solvent like AcOEt, EtOHor MeOH, preferably at atmospheric pressure of hydrogen, gives thetrans-amino ester D-5. Amidation with an acid of Structure A-4 (L¹=OH)in the presence of an amide-coupling reagent such as TBTU, HATU, COMU,EDC, DCC, T₃P or PyBOP and a base like DIPEA or TEA in a solvent such asDCM, MeCN or DMF; or the corresponding acyl chloride (L¹=Cl) and a baselike DIPEA or TEA in a solvent like DCM gives the corresponding amideD-6. The [S,S] trans-amido ester D-6, which corresponds to theintermediate B-3 in Scheme B, can be transformed into the final compoundof formula (I) by following the sequence ester hydrolysis, amideformation, cleavage of the Boc group and N-alkylation as described inscheme B. The same sequence can be used for the synthesis of [R,R]3,4-disubstitued piperidines by starting with (R)-(+)-α-methylbenzylamine as a chiral auxiliary.

Alternatively [S,S] 3,4-disubstitued piperidines may be prepared asillustrated in Reaction Scheme E by changing the sequence of reactionsshown in Scheme D. The predominantly cis-amino ester D-3 can be preparedas described before. Hydrogenolysis of the benzyl group as describedbefore gives the predominantly cis-amino ester E-4. Amidation with anacid of Structure A-4 (L¹=OH) or the corresponding acyl chloride(L¹=Cl), using the conditions described before gives the correspondingpredominantly cis amido ester E-5. Epimerization to the trans-amidoester B-3 can be done using the conditions described before. Thetrans-amido ester B-3 can be transformed into the final compound offormula (I) as described in scheme B. The same sequence can be used forthe synthesis of [R,R] 3,4-disubstitued piperidines by starting with(R)-(+)-α-methyl benzylamine as a chiral auxiliary.

Compounds of Structure 1 may alternatively be prepared from the transamido ester B-3. The intermediate B-3 is Boc-deprotected as describedbefore to give the corresponding amine F-1 which is is N-alkylated asdescribed before for A-2, to give the N-alkyl piperidine F-2. TheN-substituted alkyl (3R*,4R*)-4-amido-piperidine-3-carboxylate ester F-2can be hydrolysed to the acid 1 by treatment with a base as describedfor C-1 before.

Compounds of formula (I) may alternatively be prepared as illustrated inReaction Scheme G. A commercially available alkyl4-((tert-butoxycarbonyl)amino)piperidine-3-carboxylate G-1 isC-alkylated at position 3 by treatment with an alkyl halogenide in thepresence of a base like potassium carbonate in a solvent like acetone attemperature between 0° C. and reflux to give the keto ester G-2. Theenamine G-3 can be prepared as described before. Reduction of theenamine G-3 as described before gives the trans-amino ester G-4.Hydrogenolysis of the benzyl group as described before gives thetrans-amino ester G-5. Amidation with an acid of Structure A-4 (L¹=OH);or the corresponding acyl chloride (L¹=Cl), as described before givesthe corresponding amide G-6, which can be transformed into the finalcompound of formula (I) by following the sequence described in scheme B.The ester G-6 is saponified into the acid G-7 which is condensed with anamine 2. The resulting bis amide G-8 can be deprotected to give thepiperidine G-9 which is finally N-alkylated to give the compound offormula (I).

Alternatively the trans-amido ester intermediate B-3 can be prepared byheating the keto ester 13-1 with ammonia or ammonium acetate in MeOH attemperature between RT and refluxing. Reduction of the enamine H-1 asdescribed before gives the amino ester H-2 as a cis/trans mixture.Amidation of H-2 with an acid of Structure A-4 (L¹=OH); or thecorresponding acyl chloride (L¹=Cl), as described before gives thecorresponding amide H-3 as a cis/trans mixture. Epimerization to thetrans-amido ester B-3 can be done by treatment of H-3 with a base asdescribed before. The trans-amido ester B-3 can be transformed into thefinal compound of formula (I) by following the sequence as described inscheme B.

Alternatively [S,S] 3,4-disubstitued piperidines may be prepared asillustrated in Reaction Scheme I. The cis-amino ester E-4 can betransformed into the corresponding cis 4-benzylcarbamate derivative 1-1by treatment with N-(benzyloxycarbonyloxy) succinimide in THF or DCM.Epimerization to the trans-amido ester 1-2 can be done using theconditions described before. 1-2 can be transformed into theintermediate 1-6 by following the sequence ester hydrolysis, amideformation, cleavage of the Boc group and N-alkylation as described inscheme B. The benzylcarbamate protecting group is removed by catalytichydrogenation in the presence of Pd on charcoal or Pd hydroxide in asolvent like AcOEt, EtOH or MeOH, preferably at atmospheric pressure ofhydrogen, to yield the 4-trans-amino-3-carboxamide I-7. Amidation of 1-7with an acid of Structure A-4 (L¹=OH) or the corresponding acyl chloride(L¹=Cl), using the conditions described before gives the final compoundof formula (I) as described in scheme B. The same sequence can be usedfor the synthesis of [R,R] 3,4-disubstitued piperidines by starting with(R)-(+)-α-methyl benzylamine as a chiral auxiliary.

Whenever the compounds of formula (I) are obtained in the form ofmixtures of enantiomers, the enantiomers can be separated using methodsknown to one skilled in the art: e.g. by formation and separation ofdiastereomeric salts or by HPLC over a chiral stationary phase such as aRegis Whelk-O1(R,R) (10 μm) column, a Daicel ChiralCel OD-H (5-10 μm)column, or a Daicel ChiralPak IA (10 μm), IA, IB, IC, IE, or IF (5 μm)or AD-H (5 μm) column. Typical conditions of chiral HPLC are anisocratic mixture of eluent A (EtOH, in presence or absence of an aminesuch as triethylamine or diethylamine) and eluent B (heptane), at a flowrate of 0.8 to 150 mL/min.

The following examples are provided to illustrate the invention. Theseexamples are illustrative only and should not be construed as limitingthe invention in any way.

Experimental Part I. Chemistry

All temperatures are stated in ° C. Commercially available startingmaterials were used as received without further purification. Unlessotherwise specified, all reactions were carried out in oven-driedglassware under an atmosphere of nitrogen or argon. Compounds werepurified by flash column chromatography on silica gel or by preparativeHPLC. Compounds described in the invention are characterised by LC-MSdata (retention time t_(R) is given in min; molecular weight obtainedfrom the mass spectrum is given in g/mol) using the conditions listedbelow. In cases where compounds of the present invention appear as amixture of conformational isomers, particularly visible in their LC-MSspectra, the retention time of the most abundant conformer is given.

NMR Spectroscopy

Bruker Avance II spectrometer equipped with a 400 MHz (¹H) Ultrashield™Magnet and a BBO 5 mm probehead or a PAXTI 1 mm probehead, or a BrukerAvance III HD Ascend 500 MHz (¹H), magnet equiped with DCH cryoprobe.Chemical shifts (δ) are reported in parts per million (ppm) relative toproton resonances resulting from incomplete deuteration of the NMRsolvent, e.g. for dimethylsulfoxide δ(H) 2.49 ppm, for chloroform δ(H)7.24 ppm. The abbreviations s, d, t, q and m refer to singlet, doublet,triplet, quartet, multiplet and br to broad, respectively. Couplingconstants J are reported in Hz. In case NMR spectra are measured using 1mm Microprobe® tubes and a PAXTI 1 mm probehead, the compounds aredissolved in non-deuterated DMSO. The spectra are then measured withdouble irradiation for suppression of the DMSO and H₂O peaks. In thatcase only a selection of representative NMR peaks of the compound isgiven.

Quality Control (QC) Analytical LC-MS: Equipment and Conditions:

Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector,DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Columns:Acquity UPLC CSH C18 1.7 μm 2.1×50 mm or Acquity UPLC HSS T3 C18 1.8 μm2.1×50 mm from Waters, thermostated in the Acquity UPLC Column Managerat 60° C. Eluents: A1: H2O+0.05% FA; B1: AcCN+0.045% FA. Method:Gradient: 2% B 98% B over 2.0 min. Flow: 1.0 mL/min. Detection: UV 214nm and ELSD, and MS, tR is given in min.

Analytical LC-MS Equipment:

Binary gradient pump Agilent G4220A or equivalent with mass spectrometrydetection (single quadrupole mass analyser, Thermo Finnigan MSQPIus orequivalent)

Conditions:

Method A (acidic conditions): Column: Zorbax SB-aq (3.5 μm, 4.6×50 mm);conditions: MeCN [eluent A]; water+0.04% TFA [eluent B]; gradient: 95%B→5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.

Method B (acidic conditions): Column: Waters XBridge C18 (2.5 μm, 4.6×30mm); conditions: MeCN [eluent A]; water+0.04% TFA [eluent B]; gradient:95% B→5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.

Method C (acidic conditions): Column: Waters BEH C18 (2.5 μm, 3.0×50mm); conditions: MeCN [eluent A]; water+0.04% TFA [eluent B]; gradient:95% B→5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.

Method D (basic conditions): Column: Waters BEH C18 (2.5 μm, 3.0×50 mm);conditions: MeCN [eluent A]; H₂O+0.05% NH₄OH [eluent B]; gradient: 95%B→5% B over 1.9 min (flow 1.6 mL/min), Detection: UV/Vis+MS.

Preparative LC-MS Equipment:

Binary gradient pump Gilson 333/334 or equivalent with mass spectrometrydetection (single quadrupole mass analyser, Thermo Finnigan MSQPIus orequivalent)

Conditions:

Method E (basic conditions): Column: Waters XBridge C18 (10 μm, 30×75mm); conditions: MeCN [eluent A]; water+0.5% NH₄OH (25% aq.) [eluent B];gradient: 95% B 5% B, over 6.5 min (flow: 75 mL/min). Detection:UV/Vis+MS

Method F (acidic conditions): column: Waters XBridge C18 (10 μm, 30×75mm); conditions: MeCN [eluent A]; water+0.5% formic acid [eluent B];gradient: 95% B→5% B, over 6.5 min (flow: 75 mL/min). Detection:UV/Vis+MS

Chiral Analytical Chromatography Equipment:

HPLC: Dionex HPG-3200SD pump with a Dionex DAD-3000 UV detector.

SFC: CO₂ supply: Aurora Fusion A5 Evolution; pump: Agilent G4302A; UVdetector: Agilent G1315C.

Conditions:

HPLC: Columns: ChiralPak AY-H, 5 μm, 250×4.6 mm or Regis (R,R) Whelk-O1250×4.6 mm, 5 μm; eluent: A: Hept, 0.05% DEA, B: Ethanol, 0.05% DEA,flow 0.8 to 1.2 mL/min.

SFC Column: Regis (R,R) Whelk-O1, 4.6×250 mm, 5 μM; eluent: A: 60% CO₂,B: 40% DCM/EtOH/DEA 50:50:0.1

Chiral Preparative Chromatography Equipment:

HPLC: 2 Varian SD1 pump with a Dionex DAD-3000 UV detector.

SFC: CO₂ supply: Maximator DLE15-GG-C; pumps: 2 SSI HF CP 300; UVdetector: Dionex DAD-3000.

Conditions:

HPLC: Columns: ChiralPak IA, IB, IC, IE, or IF, 5 μm, 20×250 mm, orRegis (R,R) Whelk-O1, 21.1×250 mm, 5 μm; eluent: appropriate mixture ofA (0% to 90% Hept) and B (10% to 100% EtOH, 0.1% DEA), flow: appropriateflow of 16, 23 or 34 mL/min.

SFC: Columns: Regis (R,R) Whelk-O1, 30×250 mm, 5 μm or ChiralPak IC,30×250 mm, 5 μm; eluent: appropriate mixture of A (60% to 70% CO₂), andB (30% to 40% of DCM/EtOH/DEA 50:50:0.1), flow 160 mL/min.

Abbreviations (as Used Hereinbefore or Hereinafter)

aq. aqueousatm atmosphereBSA bovine serum albuminBoc butyloxycarbonylBB building-blockCDI carbonyl diimidazoleCOMU1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphated daysdba dibenzylidene acetoneDCC dicyclohexyl carbodiimideDCM dichloromethaneDEA diethylamineDIPEA diisopropyl-ethylamine, Hünig's base, ethyl-diisopropylamineDMAP 4-dimethylaminopyridneDMF dimethylformamideDMSO dimethylsulfoxideEDC N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimideeq. equivalent(s)Et ethylEtOAc ethyl acetateEtOH ethanolEx. example(s)h hour(s)HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateHBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHept heptaneHOBt 1-hydroxybenzotriazoleHOAT 7-Aza-1-hydroxybenzotriazoleHPLC high performance liquid chromatographyHV high vacuum conditions^(i)Bu isobutyl^(i)Pr isopropylKO^(t)Bu potassium tert-butoxideLC-MS liquid chromatography mass spectrometryLiHMDS Lithium bis(trimethylsilyl)amideLit. LiteratureMe methylMeCN acetonitrileMeOH methanolmL milliliterMTBE methyl-tert-butyl ethermin minute(s)Nr numberNaOAc sodium acetate

NBS N-Bromosuccinimide NMP N-methylpyrrolidone

^(n)Pr n-propylOAc acetatePh phenylPPh₃ triphenyl phosphinePOCl₃ Phosphorus (V) oxychlorideprep. PreparativePyBOPbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium-hexafluoro-phosphaterac racemicRT room temperatures second(s)sat. SaturatedSelectfluor® 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)SFC: supercritical fluid chromatographysoln. solutiontBu tert-butyl=tertiary butylTBTU 2-(1H-benzotriazole-1-yl)-1,2,3,3-tetramethyluroniumtetrafluoroborateTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyT₃P Propylphosphonic anhydridet_(R) retention time

Preparation of Esters and Carboxylic Acids of Structure A-4 Used for theSynthesis of Building-Blocks 1.07 to 1.17 and Examples 3.001 to 3.022A-4.01: 5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid A-4.01a:5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester

The title compound A-4.01a is prepared in analogy to the proceduredescribed in Eur. J. Org. Chem. 2006, 4852-4860, by stirring a solutionof ethyl nitroacetate (1.36 mL, 12 mmol),2-ethynyl-1,3,5-trifluorobenzene (312 mg, 2 mmol) and1,4-diazabicyclo[2.2.2]octane (0.156 mL, 1.4 mmol) in NMP (1.2 mL), at65° C. overnight. The solvent is evaporated and the product used in thenext step without further purification, LC-MS method A: t_(R)=1.07 min.

A-4.01: 5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid

To a solution of ester A-4.01a (542 mg, 2 mmol) in THF (4 mL) is addedLiOH.H₂O (12 mmol) dissolved in 10 mL water. After stirring for 64 h, a4M solution HCl (10 mmol) is added, followed by water (1.5 mL). Theprecipitated product is filtered, washed with water (2×2.5 mL) and DCM(2×2.5 mL) and dried under HV. The title compound is obtained as a whitepowder, LC-MS method A: t_(R)=0.83 min; [M+H]⁺=407.05; ¹H NMR (400 MHz,DMSO) δ: 14.3 (bs, 1H), 7.54 (t, J=9.3 Hz, 2H), 7.19 (s, 1H).

A-4.02: 5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carboxylic acidA-4.02a: 5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carboxylic acid ethylester

The title compound is prepared according to the procedure A-4.01a,starting from 2-chloro-1-ethynyl-4-fluoro-benzene; LC-MS method A:t_(R)=1.15 min.

A-4.02: 5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.01b,starting from ester A-4.02a; LC-MS method A: t_(R)=0.9 min; 1H NMR (500MHz, DMSO) δ: 8.00 (m, 1H), 7.73 (m, 1H), 7.45 (m, 1H), 7.14 (s, 1H).

A-4.03: 5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acidA-4.03a: 5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethylester

The title compound is prepared according to the procedure A-4.01a,starting from 4-chloro-1-ethynyl-2-fluoro-benzene; LC-MS method A:t_(R)=1.18 min.

A-4.03: 5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.01b,starting from ester A-4.03a; LC-MS method D: t_(R)=0.93 min; ¹H NMR (500MHz, DMSO) δ: 8.03 (m, 1H), 7.77 (m, 1H), 7.52-7.54 (m, 1H), 7.18-7.19(m, 1H).

A-4.04: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic acid A-4.04a:5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester

The title compound is prepared according to the procedure A-4.01a,starting from 2-ethynyl-1,3-difluorobenzene; LC-MS method A: t_(R)=1.06min.

A-4.04: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.01b,starting from ester A-4.04a; LC-MS method A: t_(R)=0.84 min; ¹H NMR (500MHz, DMSO) δ: 7.65 (m, 1H), 7.35 (m, 2H), 6.91 (s, 1H).

A-4.05: 3-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acidethyl ester

The title compound is prepared in analogy to the procedure described inChemMedChem 2012, 7, 1020-1030. To a solution of2,4-difluorobenzamidoxime (344 mg, 2 mmol) dissolved in THF (5 mL) isadded ethyl 2-chloro-2-oxoacetate (0.279 mL, 2.5 mmol), followed byDIPEA (0.437 mL, 2.5 mmol). The reaction mixture is stirred at 75° C.for 3 h. The mixture is then quenched with water (25 mL) and extractedwith EtOAc (25 mL). The organic layer is dried over MgSO₄, filtered andconcentrated under reduced pressure to give the desired product as ayellow solid. LC-MS method C: t_(R)=1.01 min. 1H NMR (400 MHz, DMSO) δ:8.15 (m, 1H), 7.62 (m, 1H), 7.37 (m, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.39(t, J=7.2 Hz, 3H).

A-4.06: 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic acid lithium salt

The title compound is prepared in analogy to the procedure described inChemMedChem 2012, 7, 1020-1030.

A-4.06a: Ethyl 24(2-(2,4-difluorophenyl)-2-oxoethyl)amino)-2-oxoacetate

To a solution of 2,4-difluorophenacylamine hydrochloride (415 mg, 2mmol) in DCM (8 mL) and TEA (0.591 mL, 4.2 mmol), cooled to 0° C., isadded ethyl chlorooxoacetate (0.226 mL, 2.02 mmol). The reaction mixtureis stirred 1 h30 at 0° C. and then quenched with water (10 mL),extracted twice with DCM (2×10 mL). The combined organic layers aredried over MgSO₄, and the solvent is evaporated to give the titlecompound as a brown oil. LC-MS method C: t_(R)=0.82 min; [M+H]⁺=272.20.

A-4.06b: 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic acid ethyl ester

POCl₃ (0.52 mL, 5.58 mmol) is added dropwise to a solution of A-4.06a(480 mg, 1.77 mmol), dissolved in toluene (5 mL). The mixture is stirredovernight at 110° C. After cooling the solution to 0° C., it is quenchedby dropwise addition of water (2 mL) and then it is neutralized withsat. aq. NaHCO₃ and extracted with DCM (20 mL). The organic layer isevaporated and the product is purified by prep. LC-MS method F. LC-MSmethod D: t_(R)=1.01 min; [M+H]⁺=253.98.

A-4.06: 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic acid lithium salt

To a solution of ester A-4.06b (574 mg, 2.13 mmol) in THF (10 mL) isadded 1 M LiOH aq. sol. (6.4 mL, mg, 6.4 mmol). After stirring for 1hour, the solvents are evaporated under reduced pressure to give thetitle compound as a beige powder, LC-MS method D: t_(R)=0.65 min;[M+H]⁺=226.30.

A-4.07: 5-(2,4-Difluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic acidlithium salt A-4.07a:5-(2,4-Difluoro-phenyl)-[1,3,4]-oxadiazole-2-carboxylic acid ethyl ester

The title compound is prepared in analogy to the procedure described inChemMedChem 2012, 7, 1020-1030.

To a solution of 2,4-difluorobenzoic acid hydrazide (2.65 g, 15.4 mmol)in 50 mL DCM is added TEA (9.67 mL, 69.4 mmol). The mixture is cooled to0° C. and ethyl chlorooxoacetate (2.44 mL, 21.2 mmol) is added. Themixture is stirred 2 h at 0° C. Then, toluene-4-sulfonyl chloride (4.40g, 23.1 mmol) is added and stirring is continued overnight at RT. A sat.aq. NaHCO₃ solution (50 mL) is added and the reaction mixture isextracted twice with DCM (2×50 mL). The combined organic layers aredried over MgSO₄, filtered and evaporated. The residue is purified byflash chromatography using a gradient of eluent heptane/AcOEt (9:1 to4:1) to give a light yellow solid. LC-MS method A: t_(R)=0.80 min;[M+H]⁺=255.13, [M+H+MeCN]⁺=296.10.

A-4.07: 5-(2,4-Difluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic acidlithium salt

To a solution of ester A-4.07a (25.4 mg, 0.1 mmol) in THF (0.2 mL) isadded LiOH hydrate (5 mg, 0.1 mmol) dissolved in water (0.2 mL). Afterstirring for 1 hour, the solvents are evaporated under reduced pressureto give the title compound as a white powder, LC-MS method D: t_(R)=0.41min; ¹H NMR (400 MHz, DMSO) δ: 8.07 (m, 1H), 7.58 (m, 1H), 7.34 (m, 1H).

A-4.08: 1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acidA-4.08a: 1(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acidethyl ester

To a solution of ethyl 2-diazo-3-oxopropanoate (obtained according toprocedure described in Journal of the American Chemical Society, 2011,133(4), 1044-1051) (1.6 g, 8.85 mmol) in EtOH (3.15 mL) is added glacialacetic acid (1.27 mL, 22.1 mmol) followed by 2,4-difluoroaniline (1.22g, 9.47 mmol). After stirring overnight, the reaction mixture isconcentrated and the residue is diluted with cold water (40 mL). Theprecipitate is filtered, washed with cold water (10 mL) and dried underHV to afford the title compound as a beige solid. LC-MS method A:t_(R)=0.8 min; [M+H]⁺=254.12.

A-4.08: 1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid

To a solution of ester A-4.08a (1.93 g, 7.62 mmol) in THF (16 mL) isadded LiOH hydrate (11.4 mmol) dissolved in water (16 mL). Afterstirring for 45 min, THF is evaporated and the aq. residue is cooled to0° C. A 1M HCl solution is added until pH=2. The precipitated product isfiltered, washed with water (15 mL), and dried under HV. The titlecompound is obtained as a beige powder, LC-MS method A: t_(R)=0.61 min;[M+H]⁺=225.96, [M+H+MeCN]⁺=267.10.

A-4.09: 5-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-3-carboxylic acidA-4.09a: 5-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-3-carboxylic acidethyl ester

The title compound is prepared following a procedure analogous to thatdescribed in WO 2012/168315. Ethyl 2-amino(hydroxyimino)acetate (2.27 g,16.7 mmol) dissolved in 2,6-dimethylpyridine (5.88 mL, 50 mmol) istreated dropwise with a solution of 2,4-difluorobenzoyl chloride (1.39mL, 11.1 mmol) in DCM (30 mL). The reaction mixture is stirredovernight. The beige suspension is dissolved with DCM (150 mL) andwashed with water (50 mL), then 1M HCl (50 mL) and brine (50 mL). Theorganic layer is dried over MgSO₄, filtered and the solvent evaporated.The intermediate white powder ethyl2-(2,4-difluorobenzamido)-2-(hydroxyimino)acetate is then heated 1 h at200° C. in a DrySyn metal block (from Asynt Ltd.). After cooling down,the title compound is purified by flash chromatography using a gradientof 2% to 20% EtOAc in n-heptane as eluent. LC-MS method A: t_(R)=0.85min; [M+H]⁺=255.02.

A-4.09: 5-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-3-carboxylic acid

To compound A-4.09a (3.84 g, 14.1 mmol) dissolved in THF (25 mL) andwater (25 mL), is added LiOH.H2O (799 mg, 19 mmol) and the mixture isstirred for 1 h. THF is evaporated and the aq. phase is diluted withwater (50 mL), cooled to 0° C. and acidified to pH 2-3 with an aq. 1MHCl solution. The precipitated product is filtered, washed with water(20 mL) and dried under HV. LC-MS method A: t_(R)=0.57; 1H NMR (400 MHz,DMSO) δ: 8.27 (m, 1H), 7.67 (m, 1H), 7.41 (m, 1H).

A-4.10: 3-(2,4-Difluoro-phenyl)-isoxazole-5-carboxylic acid A-4.10a:3-(2,4-Difluoro-phenyl)-isoxazole-5-carboxylic acid ethyl ester

The title compound is prepared in analogy to the preparation describedin Bioorganic & Medicinal Chemistry Letters 18 (2008), 4521-4524.

2,4-Difluorobenzaldehyde oxime (prepared according to proceduredescribed in Bioorganic & Medicinal Chemistry Letters, 20 (2010),1272-1277) (4.25 g, 24.4 mmol) is dissolved in THF (50 mL). Thenpyridine (2.46 mL, 30.5 mmol) is added. The mixture is heated up to 60°C. and N-chlorosuccinimide (3.58 g, 26.8 mmol) is added. The reactionmixture is stirred at 60° C. for 45 min and then TEA (4.11 mL, 29.2mmol) and ethyl propiolate (2.72 mL, 26.8 mmol) are added. The reactionmixture is stirred overnight at 60° C. and then concentrated under HV.The residue is taken up in DCM (100 ml) and diluted with aq. 1M HCl (100mL). The separated organic phase is washed with water (100 mL). Theorganic phase is dried over

MgSO₄, filtered and the solvent is evaporated under HV. The crude ispurified by flash chromatography using n-Heptan/EtOAc 9/1 as eluent toyield the title compound. LC-MS method A: t_(R)=0.92 min.

A-4.10: 3-(2,4-Difluoro-phenyl)-isoxazole-5-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.10a. LC-MS method A: t_(R)=0.68 min. 1HNMR (400 MHz, DMSO) δ: 14.48 (bs, 1H), 7.99-8.05 (m, 1H), 7.50-7.56 (m,2H), 7.30 (m, 1H).

A-4.11: 4-Fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acidA-4.11a: 4-Fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid methylester

To a solution of methyl 5-(4-fluorophenyl)isoxazole-3-carboxylate (246mg, 1.11 mmol) in tetramethylene sulfone (4 mL, 41.6 mmol) is addedSelectfluor® (498 mg, 1.33 mmol). The reaction mixture is stirred at150° C. overnight. DCM (20 mL) and water (20 mL) are added. Afterseparation of the layers, the aq. phase is extracted with DCM (20 mL).The combined organic layer are washed with water (3×20 mL), dried overMgSO₄, filtered and evaporated. The crude product is purified by flashchromatography using n-heptane to n-heptane/ethyl acetate (7:3) aseluent to yield the title compound. LC-MS method A: t_(R)=1.01 min.

A-4.11: 4-Fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.11a. LC-MS method A: t_(R)=0.79 min.

A-4.12: 5-(2,4-Difluoro-phenyl)-4-fluoro-isoxazole-3-carboxylic acidA-4.12a: 5-(2,4-Difluoro-phenyl)-4-fluoro-isoxazole-3-carboxylic acidethyl ester

The title compound is prepared according to the procedure A-4.11,starting from 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid ethylester. LC-MS method A: t_(R)=1.01 min.

A-4.12: 5-(2,4-Difluoro-phenyl)-4-fluoro-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.12a. LC-MS method A: t_(R)=0.76 min.

A-4.13: 5-(2-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acidA-4.13a: 2,4-Dioxo-4-(2-trifluoromethyl-phenyl)-butyric acid ethyl ester

To a solution of sodium ethoxide (21% in EtOH) (2.16 mL, 5.79 mmol) atRT is added diethyl oxalate (0.929 mL, 6.84 mmol) in one portion. Asolution of 2-(trifluoromethyl)acetophenone (0.797 mL, 5.26 mmol) in THF(3 mL) is added dropwise to the reaction mixture. The brown RM isstirred 1 h at RT. The reaction is slowly quenched by dropwise additionof 1M HCl (8 mL). THF is evaporated. The residue is partitioned betweenDCM (10 mL) and sat. NaHCO₃ solution (10 mL) and the aq. phase isextracted with DCM (2×10 mL), dried over MgSO₄, filtered and evaporatedto yield the title compound as an orange oil; LC-MS method A: t_(R)=1.00min. [M+H]⁺=289.16.

A-4.13b: 5-(2-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethylester

Hydroxylamine hydrochloride (0.372 mL, 5.46 mmol) is added to a solutionof 2,4-dioxo-4-(2-trifluoromethyl-phenyl)-butyric acid ethyl ester (1500mg, 5.2 mmol) in EtOH (20 mL). The mixture is heated to 70° C.overnight. To the hot mixture, water (10 mL) is added dropwise. Afteraddition, the mixture is allowed to cool down to RT. DCM (10 mL) andsat. NaHCO₃ solution (10 mL) are added and the aq. phase is extractedwith DCM (2×10 mL), dried over MgSO₄, filtered and evaporated. The crudeproduct is purified by LC-MS method E. LC-MS method A: t_(R)=1.01 min.[M+H]⁺=286.17.

A-4.13: 5-(2-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.13b. LC-MS method A: t_(R)=0.80 min.[M+H+MeCN]⁺=299.13.

A-4.14: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic acid A-4.14a:4-(2,6-Difluoro-phenyl)-2,4-dioxo-butyric acid ethyl ester

The title compound is prepared according to the procedure A-4.13a,starting from 1-(2,6-difluorophenyl)ethan-1-one. LC-MS method A:t_(R)=1.00 min.

A-4.14b: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester

The title compound is prepared according to the procedure A-4.13b,starting from building block A-4.14a. LC-MS method A: t_(R)=0.97 min.[M+H]⁺=254.20.

A-4.14: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.14b. LC-MS method A: t_(R)=0.74 min.[M+H+MeCN]⁺=267.14

A-4.15: 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acidA-4.15a: 2,4-Dioxo-4-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester

The title compound is prepared according to the procedure A-4.13a,starting from 1-(4-(trifluoromethyl)phenyl)ethan-1-one. LC-MS method A:t_(R)=1.05 min. [M+H]⁺=288.96.

A-4.15b: 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethylester

The title compound is prepared according to the procedure A-4.13b,starting from building block A-4.15a. LC-MS method A: t_(R)=1.05 min.[M+H+MeCN]⁺=327.06.

A-4.15: 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.15b. LC-MS method A: t_(R)=0.85 min.

A-4.16: 5-(3-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid

A-4.16a: 2,4-Dioxo-4-(3-trifluoromethyl-phenyl)-butyric acid ethyl esterThe title compound is prepared according to the procedure A-4.13a,starting from 1-(3-(trifluoromethyl)phenyl)ethan-1-one. LC-MS method A:t_(R)=1.05 min. [M+H]⁺=289.17.

A-4.16b: 5-(3-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid ethylester

The title compound is prepared according to the procedure A-4.13b,starting from building block A-4.16a. LC-MS method A: t_(R)=1.05 min.[M+H]⁺=286.18.

A-4.16: 5-(3-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.16b. LC-MS method A: t_(R)=0.85 min.

A-4.17: 5-(2,3,4-Trifluoro-phenyl)-isoxazole-3-carboxylic acid A-4.17a:2,4-Dioxo-4-(2,3,4-trifluoro-phenyl)-butyric acid ethyl ester

The title compound is prepared according to the procedure A-4.13a,starting from 1-(2,3,4-trifluorophenyl)ethan-1-one. LC-MS method A:t_(R)=1.04 min. [M+H]⁺=275.17.

A-4.17b: 5-(2,3,4-Trifluoro-phenyl)-isoxazole-3-carboxylic acid ethylester

The title compound is prepared according to the procedure A-4.13b,starting from building block A-4.17a. LC-MS method A: t_(R)=1.02 min.

A-4.17: 5-(2,3,4-Trifluoro-phenyl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.17b. LC-MS method A: t_(R)=0.79 min.

A-4.18: 5-(5-Fluoro-pyridin-2-yl)-isoxazole-3-carboxylic acid A-4.18a:4-(5-Fluoro-pyridin-2-yl)-2,4-dioxo-butyric acid ethyl ester

The title compound is prepared according to the procedure A-4.13a,starting from 1-(5-fluoropyridin-2-yl)ethan-1-one. LC-MS method A:t_(R)=0.89 min. [M+H]⁺=240.25.

A-4.18b: 5-(5-Fluoro-pyridin-2-yl)-isoxazole-3-carboxylic acid ethylester

The title compound is prepared according to the procedure A-4.13b,starting from building block A-4.18a. LC-MS method A: t_(R)=0.85 min.[M+H]⁺=237.28.

A-4.18: 5-(5-Fluoro-pyridin-2-yl)-isoxazole-3-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.18b. LC-MS method A: t_(R)=0.59 min.[M+H]⁺=209.37.

A-4.19: 4-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic acid A-4.19a:4-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic acid ethyl ester

2-Acetoxy-2′,4′-difluoroacetophenone (200 mg, 0.934 mmol) is dissolvedin p-xylene (10 mL). Ethyl oxamate (437 mg, 3.74 mmol) and borontrifluoride diethyl etherate (0.248 mL, 0.934 mmol) are added. Thereaction mixture is heated to 150° C. for 20 h.

The reaction mixture is diluted with EtOAc (40 mL) and washed withsaturated NaHCO₃ solution (20 mL). After separation of the layers theaq. layer is extracted with EtOAc (2×20 mL). The combined organic layersare dried over MgSO₄, filtered and evaporated. The crude product ispurified by LC-MS method E. LC-MS method A: t_(R)=0.96 min.[M+H]⁺=254.11.

A-4.19: 4-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic acid

The title compound is prepared according to the procedure A-4.09,starting from building block A-4.19b. LC-MS method A: t_(R)=0.69 min.[M+H]⁺=226.23.

A-4.20: 1-(2,4,6-Trifluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acidA-4.20a: 1-(2,4,6-Trifluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acidethyl ester

The title compound is prepared according to the procedure A-4.08a,starting from ethyl 2-diazo-3-oxopropanoate and 2,4,6-trifluoroaniline.LC-MS method A: t_(R)=0.84 min. [M+H]⁺=272.29.

A-4.20: 1-(2,4,6-Trifluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid

The title compound is prepared according to the procedure A-4.08,starting from building block A-4.20a. LC-MS method A: t_(R)=0.65 min.[M+H]⁺=244.24.

A-4.21: 5-(2,4-Difluoro-phenyl)-isothiazole-3-carboxylic acid A-4.21a:5-(2,4-Difluorophenyl)-3-methylisothiazole

Pd(PPh₃)₄ (892 mg, 0.77 mmol) is added to a degassed solution of5-bromo-3-methyl-isothiazole (1446 mg, 7.72 mmol),2,4,difluorophenylboronic acid (1462 mg, 9.26 mmol) and K₃PO₄ (8355 mg,748 mmol) in dioxane (64 mL) and water (10 mL). The resulting solutionis stirred for 24 h at 90° C. under argon. The resulting mixture isdiluted with DCM (100 mL) and washed with H₂O (100 mL). The organiclayer is separated and the aq. phase is extracted twice with DCM (2×100mL). The combined organic layers are dried over anhydrous sodium sulfateand filtered. The resulting mixture is concentrated under vacuum. Thecrude is purified by flash silicagel chromatography using n-heptan ton-hepan/EtOAc 85:15 as eluent to yield the title compound as a whitepowder. LC-MS method A: t_(R)=1.01 min. [M+H]⁺=212.19.

A-4.21b: 3-Bromomethyl-5-(2,4-difluoro-phenyl)-isothiazole

A mixture of 5-(2,4-difluorophenyl)-3-methylisothiazole (1042 mg, 4.93mmol), N-br omosuccinimide (966 mg, 5.43 mmol) and benzoyl peroxide (119mg, 0.49 mmol) in trifluorotoluene (40 mL) is refluxed for 30 h. MoreNBS (500 mg, 2.8 mmol), benzoyl peroxide (80 mg, 0.33 mmol) are addedand the mixture is then refluxed 2 h. It is diluted with DCM (100 mL)and water (100 mL). The organic layer is separated and the aq. layer isextracted with DCM (100 mL). The combined organic layers are dried overanhydrous sodium sulfate, concentrated, and purified by flash silicagelchromatography using DCM/n-heptan 1:1 as eluent to yield the titlecompound as a sticky oil. LC-MS method A: t_(R)=1.06 min. [M+H]⁺=292.09.

A-4.21c: 5-(2,4-Difluoro-phenyl)-isothiazole-3-carboxylic acid ethylester

A suspension of 3-bromomethyl-5-(2,4-difluoro-phenyl)-isothiazole (1150mg, 3.96 mmol) in water (10 mL) at reflux is treated with small portionsof potassium permanganate (860 mg, 5.39 mmol) over 30 minutes. Thereaction mixture is stirred for 5 h. During this time the purplecoloration turns to a colorless liquid with a black suspension, which isfiltered through a Whatmann GF/A fitled and evaporated. The crude isdiluted with DCM (25 mL) and sat. HCl 1N (25 mL) The aq. phase isextracted thrice with DCM (3×25 mL). The combined organic extracts aredried over MgSO₄, filtered and concentrated in vacuo. The crude containsmainly starting material. The black residue is diluted in ethanol (200ml) and 4N HCl in dioxane (25 mL) is added. The reaction mixture isrefluxed overnight. The black slurry turns to a clear solution and thecorresponding ester has been formed. The solution is concentrated invacuo. The crude is purified by flash silicagel chromatography usingn-heptan to n-heptan/EtOAc 95:5 as eluent to yield the title compound asa white powder. LC-MS method A: t_(R)=1.06 min. [M+H]⁺=270.17.

A-4.21: 5-(2,4-Difluoro-phenyl)-isothiazole-3-carboxylic acid

A solution of 5-(2,4-difluoro-phenyl)-isothiazole-3-carboxylic acidethyl ester (216 mg, 0.8 mmol) in EtOH/1N aq. NaOH (4 mL) is stirred for24 h at RT. The reaction mixture is washed with EtOAc (10 mL). The aq.phase is made acidic with 1N HCl (5 mL) and then extracted five timeswith DCM (5×10 mL). The combined extracts are dried over MgSO₄, filteredand concentrated in vacuo to yield the title compound as a white powder.LC-MS method A: t_(R)=0.84 min. [M+H]⁺=241.83.

General Method a for the Synthesis of Compounds of Formula (I) BuildingsBlocks Preparation of Building Blocks of Structure 1

BB 1.01:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.01a:rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylicacid methyl ester

To a solution ofrac-(3R*,4R*)-4-tert-butoxycarbonylamino-piperidine-3-carboxylic acidmethyl ester (3.0 g, 11.3 mmol) in DCM (56.4 mL) at RT is addedcyclohexanone (1.42 mL, 13.5 mmol) followed by acetic acid (0.966 mL,16.9 mmol) and sodium triacetoxyborohydride (3.39 g, 15.2 mmol). Afterstirring for 5 h, additional cyclohexanone (0.23 mL, 2.3 mmol), aceticacid (0.17 mL, 2.8 mmol) and sodium triacetoxyborohydride (590 mg, 2.8mmol) are added. The reaction mixture is stirred overnight. The reactionmixture is diluted with DCM (200 mL) and treated with aq. sat. NaHCO₃(250 mL). The organic phase is dried over MgSO₄ and evaporated. Thecrude title compound is used in the next step without furtherpurification; LC-MS method D t_(R)=1.09 min; [M+H]⁺=341.19.

1.01b: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic acidmethyl ester

rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylicacid methyl ester 1.01a (3.85 g, 11.3 mmol) is dissolved in MeOH (56.5mL). A 4M solution of HCl in dioxane (56.5 mL, 226 mmol) is added andthe reaction is stirred for 1 h. The reaction mixture is concentrated,dissolved in DCM (250 mL) and treated with aq. sat. NaHCO₃ (200 mL). Theorganic layer is separated and the aq. phase is extracted with DCM (150mL). The combined organic layers are dried over MgSO₄ and evaporated.The crude title compound is obtained as a yellow oil; LC-MS method Dt_(R)=0.79 min; [M+H]⁺=241.20.

1.01c:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

To a solution ofrac-(3R*,4R*)-4-amino-1-cyclohexyl-piperidine-3-carboxylic acid methylester 1.01b (2.64 g, 10.4 mmol) in DMF (56.7 mL) at RT is added5-(2,4-difluorophenyl)isoxazole-3-carboxylic Acid (2.42 g, 10.4 mmol).DIPEA (5.83 mL, 33.4 mmol) is then added followed by HATU (4.16 g, 10.9mmol). The reaction mixture is stirred overnight (17 h). The reactionmixture is concentrated, dissolved in DCM (300 mL) and treated with aq.sat. NaHCO₃(225 mL). The organic layer is dried over MgSO₄ andevaporated. The crude residue is purified by prep. LC-MS under basicconditions (method E). The title compound is obtained as white powder;LC-MS method D t_(R)=1.15 min; [M+H]⁺=448.19.

1.01:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester 1.01c (2.24 g, 5 mmol) is dissolved in THF (30.6 mL)at RT. Aq. 1M NaOH solution (15 mL, 15 mmol) is then added and themixture stirred for 6.5 h. The reaction mixture is acidified to aroundpH=3 with a 2M HCl solution (7.75 mL) and evaporated. The resultingsuspension is filtered, washed twice with water (2×4 mL) and dried underHV. The title compound is obtained as a white powder; LC-MS method Dt_(R)=0.61 min; [M+H]⁺=433.89.

Preparation of Building-Blocks of Structure 1 Used as Intermediates inthe Preparation of Examples 1.001 to 1.199

The following intermediates are prepared in analogy to BB 1.01:

BB 1.02:rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid 1.02c:rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.01b and building block A-4.08; LC-MSmethod D: t_(R)=1.03 min; [M+H]⁺=448.15.

1.02:rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.02c; LC-MS method D: t_(R)=0.54 min;[M+H]⁺=433.88.

BB 1.03:rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid 1.03a:rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopentyl-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01a,starting fromrac-(3R*,4R*)-4-tert-butoxycarbonylamino-piperidine-3-carboxylic acidmethyl ester and cyclopentanone; LC-MS method D: t_(R)=1.0 min;[M+H]⁺=327.18.

1.03b: rac-(3R*,4R*)-4-Amino-1-cyclopentyl-piperidine-3-carboxylic acidmethyl ester

The title compound is prepared according to the procedure 1.01b,starting from building block 1.03a; LC-MS method D: t_(R)=0.71 min;[M+H]⁺=227.18.

1.03c:rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.03b and building block A-4.08; LC-MSmethod D: t_(R)=0.95 min; [M+H]⁺=433.9.

1.03:rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.03c; LC-MS method D: t_(R)=0.49 min;[M+H]⁺=420.07.

BB 1.04:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid 1.04a:rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopropylmethyl-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01a,starting fromrac-(3R*,4R*)-4-tert-Butoxycarbonylamino-piperidine-3-carboxylic acidmethyl ester and cyclopropanecarbaldehyde; LC-MS method D: t_(R)=0.94min; [M+H]⁺=313.18.

1.04b: rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01b,starting from building block 1.04a; LC-MS method D: t_(R)=0.64 min;[M+H]⁺=213.21.

1.04c:rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.08; LC-MSmethod D: t_(R)=0.89 min; [M+H]⁺=420.1.

1.04:rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.04c; LC-MS method D: t_(R)=0.48 min;[M+H]⁺=406.09.

BB 1.05:rac-(3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylicacid 1.05a:rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01a,starting fromrac-(3R*,4R*)-4-tert-Butoxycarbonylamino-piperidine-3-carboxylic acidmethyl ester and 2-methyl-cyclopentanone; LC-MS method D: t_(R)=1.16min; [M+H]⁺=341.2.

1.05b:rac-(3R*,4R*)-4-Amino-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01b,starting from building block 1.05a; LC-MS method D: t_(R)=0.83 min;[M+H]⁺=241.19.

1.05c:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.05b and building block A-4.08; LC-MSmethod D: t_(R)=1.08 min; [M+H]⁺=448.15.

1.05:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.05c; LC-MS method D: t_(R)=0.53 min;[M+H]⁺=433.82.

BB 1.06:rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

1.06c:rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester:

The title compound is prepared according to the procedure 1.01c,starting from building block 1.03b and building block A-4.01; LC-MSmethod D: t_(R)=1.06 min; [M+H]⁺=452.13.

1.06:rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.06c; LC-MS method D: t_(R)=0.55 min; [M+H]⁺=438.1.

BB 1.07:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.07c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.01; LC-MSmethod D: t_(R)=1.0 min; [M+H]⁺=438.11.

1.07:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.07c; LC-MS method D: t_(R)=0.53 min;[M+H]⁺=424.09.

BB 1.08:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.08c:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.05b and building block A-4.01; LC-MSmethod D: t_(R)=1.09 min; [M+H]⁺=448.14.

1.08:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.08c; LC-MS method D: t_(R)=0.53 min;[M+H]⁺=433.82.

BB 1.09:rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid 1.09c:rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.01b and building block A-4.10; LC-MSmethod D: t_(R)=1.11 min; [M+H]⁺=448.14.

1.09:rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.09c; LC-MS method D: t_(R)=0.58 min;[M+H]⁺=433.88.

BB 1.10:rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid 1.10c:rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.03b and building block A-4.10; LC-MSmethod D: t_(R)=1.03 min; [M+H]⁺=433.88.

1.10:rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.10c; LC-MS method D: t_(R)=0.54 min;[M+H]⁺=420.12.

BB 1.11:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.11c:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.01b and building block A-4.01; LC-MSmethod D: t_(R)=1.14 min; [M+H]⁺=465.9.

1.11:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.11c; LC-MS method D: t_(R)=0.59 min; [M+H]⁺=452.1.

BB 1.12:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid 1.12c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.10; LC-MSmethod D: t_(R)=0.98 min; [M+H]⁺=420.11.

1.12:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.12c; LC-MS method D: t_(R)=0.52 min;[M+H]⁺=406.07.

BB 1.13:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid 1.13c:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.05b and building block A-4.10; LC-MSmethod D: t_(R)=1.15 min; [M+H]⁺=448.14.

1.13:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.13c; LC-MS method D: t_(R)=0.59 min;[M+H]⁺=433.87.

BB 1.14:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.14c:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.01b and building block A-4.09; LC-MSmethod D: t_(R)=1.07 min; [M+H]⁺=449.03.

1.14:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.14c; LC-MS method D: t_(R)=0.55 min; [M+H]⁺=435.1.

BB 1.15:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.15c:rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.09; LC-MSmethod D: t_(R)=0.93 min; [M+H]⁺=421.1.

1.15:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.15c; LC-MS method D: t_(R)=0.49 min;[M+H]⁺=407.05.

BB 1.16:rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.16c:rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.03b and building block A-4.09; LC-MSmethod D: t_(R)=0.99 min; [M+H]⁺=435.1.

1.16:rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.16c; LC-MS method D: t_(R)=0.51 min; [M+H]⁺=421.1.

BB 1.17:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.17c:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.05b and building block A-4.09; LC-MSmethod D: t_(R)=1.12 min; [M+H]⁺=449.02.

1.17:rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.17c; LC-MS method D: t_(R)=0.56 min; [M+H]⁺=435.1.

BB 1.18:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.01b and building block A-4.07; LC-MSmethod D: t_(R)=1.05 min; [M+H]⁺=449.08.

BB 1.19:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.19c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and5-(2,4-dichlorophenyl)-1,2-oxazole-3-carboxylic acid; LC-MS method A:t_(R)=0.75 min; [M+H]⁺=451.98.

1.19:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.19c; LC-MS method A: t_(R)=0.70 min;[M+H]⁺=438.11.

BB 1.20:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.20c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.13; LC-MSmethod A: t_(R)=0.73 min; [M+H]⁺=452.11.

1.20:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.20c; LC-MS method A: t_(R)=0.67 min;[M+H]⁺=438.22.

BB 1.21:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.21c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.14; LC-MSmethod A: t_(R)=0.68 min; [M+H]⁺=420.11.

1.21:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.21c; LC-MS method A: t_(R)=0.62 min;[M+H]⁺=406.22.

BB 1.22:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.22c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.15; LC-MSmethod A: t_(R)=0.75 min; [M+H]⁺=452.07.

1.22:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.22c; LC-MS method A: t_(R)=0.70 min;[M+H]⁺=438.25.

BB 1.23:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.23c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.16; LC-MSmethod A: t_(R)=0.74 min; [M+H]⁺=452.09.

1.23:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.23c; LC-MS method A: t_(R)=0.69 min;[M+H]⁺=438.25.

BB 1.24:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.24c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and building block A-4.17; LC-MSmethod A: t_(R)=0.72 min; [M+H]⁺=438.16.

1.24:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.24c; LC-MS method A: t_(R)=0.66 min;[M+H]⁺=424.15.

BB 1.25:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.25c:rac-(R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and5-(2-fluoro-4-methoxyphenyl)isoxazole-3-carboxylic acid; LC-MS method A:t_(R)=0.69 min; [M+H]⁺=432.29.

1.25:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.25c; LC-MS method A: t_(R)=0.67 min;[M+H]⁺=418.07.

BB 1.26:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 1.26c:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to the procedure 1.01c,starting from building block 1.04b and and building block A-4.18; LC-MSmethod A: t_(R)=0.59 min; [M+H]⁺=403.16.

1.26:rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 1.01, startingfrom building block 1.26c; LC-MS method A: t_(R)=0.54 min;[M+H]⁺=389.22.

General Procedures for the Preparation of Examples 1.001 to 1.199 MethodA:

To a solution of the respective carboxylic acid (BB 1.01 to BB 1.26)(0.1 mmol) in 1 mL DMF is added the respective amine (commerciallyavailable) (0.12 to 0.15 mmol). DIPEA (0.3 mmol; 0.6 mmol if the amineis an hydrochloride salt) is then added followed by HATU (0.105 mmol).The reaction mixture is stirred overnight at RT. The crude mixture isdirectly purified by prep. LC-MS with method E.

Method B:

To a solution of the respective carboxylic acid (BB 1.01 to BB 1.26)(0.05 mmol) in pyridine (1 mL) at RT is added the respectivecommercially available amine ((0.1 mmol). POCl₃ (0.1 mmol) is then addedand the mixture is stirred at RT for 2 h. Water (50 μL) is added and theresulting solution is evaporated. The crude residue is purified by prep.LC-MS with method E.

Method C:

To a solution of the respective carboxylic acid (BB 1.01 to BB 1.26)(0.07 mmol) and a commercially available amine (0.067 mmol) in 2 mL DCM,is added TEA (0.29 mmol) and T3P 50% in DCM (0.08 mL, 0.135 mmol). Themixture is stirred 24 h at RT and then the reaction mixture is washedwith aq. sat. NaHCO₃ and water. The organic solvent is evaporated andthe residue is purified by prep HPLC using method E.

Example 1.001:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-methyl-1-pyridin-2-yl-ethyl)-amide

To a solution ofrac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (43.3 mg, 0.1 mmol) in DMF (1 mL) is added2-(2-pyridyl)-2-propylamine dihydrochloride (41.8 mg, 0.2 mmol). DIPEA(0.055 mL, 0.32 mmol) is then added followed by HATU (39.9 mg, 0.105mmol). The reaction mixture is stirred overnight at RT. The crudemixture is directly purified by prep. LC-MS with method E. LC-MS methodD: t_(R)=1.07 min; [M+H]⁺=552.15.

Compounds of Examples 1.001a to 1.199 listed in Table 1 below areprepared by applying one of the above-mentioned general procedures A, Bor C to the building blocks BB-1.01 BB-1.26 coupled with commerciallyavailable amines of Structure 2.

Enantiomerically pure compounds are obtained by using one of the abovementioned chiral preparative chromatography methods.

TABLE 1 Examples 1.001-1.199 QC LC-MS Mass Found Example Nr SubstanceName t_(R) (min) [M + H]⁺ 1.001rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65552 carbonyl]-amino}-piperidine-3-carboxylic acid(1-methyl-1-pyridin-2-yl- ethy-amide 1.001a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.66 552.3 amino}-piperidine-3-carboxylic acid(1-methyl-1-pyridin-2-yl-ethyl)-amide (enantiomer 1) 1.001b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.66 552.2 amino}-piperidine-3-carboxylic acid(1-methyl-1-pyridin-2-yl-ethyl)-amide (enantiomer 2) 1.002rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.64551 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 1.002a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.64 551.2 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1) 1.002b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.64 551 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 2) 1.003rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71501.1 carbonyl]-amino}-piperidine-3-carboxylic acid cyclopentylamide1.004 rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid[(3R*,4R*)-1- 0.67 487.4cyclohexyl-3-(pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide 1.005rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6491.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-hydroxy-ethyl)-methyl- amide 1.006rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61491.1 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-ethyl)-amide 1.007rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71489.4 carbonyl]-amino}-piperidine-3-carboxylic acid isobutyl-amide 1.008rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66475.3 carbonyl]-amino}-piperidine-3-carboxylic acid isopropylamide 1.009rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63461.1 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.010rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58447.3 carbonyl]-amino}-piperidine-3-carboxylic acid methylamide 1.011rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61479.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-fluoro-ethyl)-amide 1.012rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.62461.3 carbonyl]-amino}-piperidine-3-carboxylic acid ethylamide 1.013rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.68487.3 carbonyl]-amino}-piperidine-3-carboxylic acidcyclopropyl-methyl-amide 1.014rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.54490.1 carbonyl]-amino}-piperidine-3-carboxylic acidcarbamoylmethyl-amide 1.015rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.56477.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-hydroxy-ethyl)-amide 1.016rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1-0.63 503.1 cyclohexyl-3-(morpholine-4-carbonyl)-piperidin-4-yl]-amide1.017rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.72489.1 carbonyl]-amino}-piperidine-3-carboxylic acidisopropyl-methyl-amide 1.018rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.42518.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2-dimethylamino-ethyl)- methyl-amide 1.019rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71519.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-ethoxy-ethyl)-methyl- amide 1.020rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66544.1 carbonyl]-amino}-piperidine-3-carboxylic acid (5-methyl-thiazol-2-ylmethyl)-amide 1.021rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.67505.1 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-ethyl)-methyl- amide 1.022rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65528.3 carbonyl]-amino}-piperidine-3-carboxylic acid(5-methyl-isoxazol-3- ylmethyl)-amide 1.023rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.4504.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2-dimethylamino-ethyl)- amide 1.024rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.67475.3 carbonyl]-amino}-piperidine-3-carboxylic acid ethyl-methyl-amide1.025rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58524.1 carbonyl]-amino}-piperidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide 1.026rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.64497.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2,2-difluoro-ethyl)-amide 1.027rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7519.3 carbonyl]-amino}-piperidine-3-carboxylic acid(3-methoxy-propyl)-methyl- amide 1.0285-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.58503.3cyclohexyl-3-(3RS)-3-hydroxy-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide (mixture of isomers) 1.029rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63528.3 carbonyl]-amino}-piperidine-3-carboxylic acid(3-methyl-isoxazol-5- ylmethyl)-amide 1.030rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3-0.62 473.3 (azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide1.031rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65544.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methyl-thiazol-4-ylmethyl)-amide 1.032rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58525.3 carbonyl]-amino}-piperidine-3-carboxylic acid(pyrimidin-2-ylmethyl)- amide 1.033rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61544.1 carbonyl]-amino}-piperidine-3-carboxylic acid (4-methyl-thiazol-5-ylmethyl)-amide 1.034rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.57525.1 carbonyl]-amino}-piperidine-3-carboxylic acid(pyrimidin-4-ylmethyl)- amide 1.035rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58514.3 carbonyl]-amino}-piperidine-3-carboxylic acid(oxazol-5-ylmethyl)-amide 1.036rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1-0.63 491.3cyclohexyl-3-(3-fluoro-azetidine-1-carbonyl)-piperidin-4-yl]-amide 1.037rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58525.3 carbonyl]-amino}-piperidine-3-carboxylic acid(pyrazin-2-ylmethyl)-amide 1.038rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71545.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-trifluoromethoxy-ethyl)- amide 1.039rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.62517.1 carbonyl]-amino}-piperidine-3-carboxylic acidmethyl-oxetan-3-ylmethyl- amide 1.040(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.62 539 amino}-piperidine-3-carboxylic acid((1RS)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.041rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61544 carbonyl]-amino}-piperidine-3-carboxylic acid[2-(2-oxo-pyrrolidin-1-yl)- ethyl]-amide 1.042rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61527.2 carbonyl]-amino}-piperidine-3-carboxylic acid(1-methyl-1H-pyrazol-3- ylmethyl)-amide 1.043rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.39513.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1H-imidazol-4-ylmethyl)- amide 1.044(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.64 517.1 amino}-piperidine-3-carboxylic acid((2RS)-tetrahydro-furan-2-ylmethyl)- amide (mixture of isomers) 1.045rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63541.2 carbonyl]-amino}-piperidine-3-carboxylic acid(1,5-dimethyl-1H-pyrazol- 3-ylmethyl)-amide 1.046a(3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-0.78 567.3 amino}-piperidine-3-carboxylic acid((1S,2R)-2-phenyl-cyclopropyl)- amide or(3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide or(3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((1S,2R)-2-phenyl-cyclopropyl)-amide or(3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid((1R,2S)-2-phenyl-cyclopropyl)-amide (1^(st) eluted enantiomer) 1.047rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66543.3 carbonyl]-amino}-piperidine-3-carboxylic acid(3-ethyl-[1,2,4]oxadiazol-5- ylmethyl)-amide 1.048rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5524.1 carbonyl]-amino}-piperidine-3-carboxylic acid(pyridin-3-ylmethyl)-amide 1.049rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.82551 carbonyl]-amino}-piperidine-3-carboxylic acid methyl-phenethyl-amide1.050rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.46524.1 carbonyl]-amino}-piperidine-3-carboxylic acid(pyridin-4-ylmethyl)-amide 1.051rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63530.3 carbonyl]-amino}-piperidine-3-carboxylic acid(thiazol-2-ylmethyl)-amide 1.052rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1-0.67 509.3cyclohexyl-3-(3,3-difluoro-azetidine-1-carbonyl)-piperidin-4-yl]-amide1.053(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.61 517.4 amino}-piperidine-3-carboxylic acid((3RS)-tetrahydro-furan-3-ylmethyl)- amide (mixture of isomers) 1.054rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61541.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2,5-dimethyl-2H-pyrazol- 3-ylmethyl)-amide 1.055rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.46563.2 carbonyl]-amino}-piperidine-3-carboxylic acid[2-(2-hydroxy-ethoxy)- ethyl]-isopropyl-amide 1.056rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8551.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2-o-tolyl-ethyl)-amide 1.057rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.78567.4 carbonyl]-amino}-piperidine-3-carboxylic acid[2-(2-methoxy-phenyl)- ethyl]-amide 1.058rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.81571 carbonyl]-amino}-piperidine-3-carboxylic acid[2-(2-chloro-phenyl)-ethyl]- amide 1.059rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.77555.1 carbonyl]-amino}-piperidine-3-carboxylic acid[2-(4-fluoro-phenyl)-ethyl]- amide 1.060(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.8 551.4 amino}-piperidine-3-carboxylic acid((2RS)-2-phenyl-propyl)-amide (mixture of isomers) 1.061(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.79 549.4 amino}-piperidine-3-carboxylic acid((1R*,2S*)-2-phenyl-cyclopropyl)- amide and(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.062rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.82551 carbonyl]-amino}-piperidine-3-carboxylic acid(2-p-tolyl-ethyl)-amide 1.063(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.59 539 amino}-piperidine-3-carboxylic acid((1RS)-1-(pyrimidin-4-yl)-ethyl)- amide (mixture of isomers) 1.064rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.74509.3 carbonyl]-amino}-piperidine-3-carboxylic acid phenylamide 1.065rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.77544.1 carbonyl]-amino}-piperidine-3-carboxylic acid(4,5-dimethyl-thiazol-2-yl)- amide 1.066rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.81551.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2-m-tolyl-ethyl)-amide 1.067rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.57510.1 carbonyl]-amino}-piperidine-3-carboxylic acid pyridin-3-ylamide1.068rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66544.1 carbonyl]-amino}-piperidine-3-carboxylic acid (4-methyl-thiazol-2-ylmethyl)-amide 1.069(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.73 592.3 amino}-piperidine-3-carboxylic acid((1RS)-2,2,2-trifluoro-1-pyridin-2-yl- ethyl)-amide (mixture of isomers)1.070 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1-0.81 563cyclohexyl-3-((3RS)-3-phenyl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide (mixture of isomers) 1.071rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63550.2 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 1.072(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.69 553 amino}-piperidine-3-carboxylic acid((R)-2-hydroxy-2-phenyl-ethyl)-amide (mixture of isomers) 1.073(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.69 553.3 amino}-piperidine-3-carboxylic acid((S)-2-hydroxy-2-phenyl-ethyl)-amide (mixture of isomers) 1.074rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.52538.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-pyridin-2-yl-ethyl)-amide 1.075rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.57552.2 carbonyl]-amino}-piperidine-3-carboxylic acidmethyl-(2-pyridin-2-yl- ethyl)-amide 1.076(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.58 491.1 amino}-piperidine-3-carboxylic acid((1RS)-2-hydroxy-1-methyl-ethyl)- amide (mixture of isomers) 1.077(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.67 511.3 amino}-piperidine-3-carboxylic acid((1RS)-2,2-difluoro-1-methyl-ethyl)- amide (mixture of isomers) 1.078(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.77 515.4 amino}-piperidine-3-carboxylic acid((1RS)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.079rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7507 carbonyl]-amino}-piperidine-3-carboxylic acid(2-fluoro-1,1-dimethyl- ethyl)-amide 1.080rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.78557.3 carbonyl]-amino}-piperidine-3-carboxylic acid(3,3,3-trifluoro-1,1- dimethyl-propyl)-amide 1.081rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63567.1 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methanesulfonyl-1,1- dimethyl-ethyl)-amide 1.082(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.64 493.3 amino}-piperidine-3-carboxylic acid((1RS)-2-fluoro-1-methyl-ethyl)- amide (mixture of isomers) 1.083(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.69 519.4 amino}-piperidine-3-carboxylic acid((1RS)-2-ethoxy-1-methyl-ethyl)- amide (mixture of isomers) 1.084(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.64 517.2 amino}-piperidine-3-carboxylic acid((3RS)-3-methyl-tetrahydro-furan-3- yl)-amide (mixture of isomers) 1.085(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.62 543 amino}-piperidine-3-carboxylic acid[(1RS)-1-(5-methyl-[1,3,4]oxadiazol- 2-yl)-ethyl]-amide (mixture ofisomers) 1.086(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.74 574 amino}-piperidine-3-carboxylic acid[(1RS)-1-(3,5-difluoro-pyridin-2-yl)- ethyl]-amide (mixture of isomers)1.087rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.73537.3 carbonyl]-amino}-piperidine-3-carboxylic acid(3,3-difluoro-1-methyl- cyclobutyl)-amide (mixture of isomers) 1.088rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63505.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2-hydroxy-1,1-dimethyl- ethyl)-amide 1.0895-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.64564cyclohexyl-3-((3RS)-3-pyridin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide (mixture of isomers) 1.090(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.61 539.4 amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)-amide (mixture of isomers) 1.091(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.77 515.4 amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.092(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.72 556.4 amino}-piperidine-3-carboxylic acid[(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]- amide (mixture of isomers) 1.093(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.79 517.4 amino}-piperidine-3-carboxylic acid((R)-1,2,2-trimethyl-propyl)-amide (mixture of isomers) 1.094(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.66 557 amino}-piperidine-3-carboxylic acid[(R)-1-(5-fluoro-pyrimidin-2-yl)-ethyl]- amide (mixture of isomers)1.095rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-0.55 461.3 4-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide1.095a(3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.55 461.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamideor (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (1^(st) elutedenantiomer) 1.096rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.5 447.2[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide 1.097rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 1433.3 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide 1.098(3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-0.55 461.3amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 1.099rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.59 465.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide1.100 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-0.58 451.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide 1.101(3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-0.63 479.3 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide (mixture of isomers) 1.102rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.62461 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.103rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.57 447 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide1.104 rac-1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid0.54 473.3[(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide1.105 rac-5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid[(3R*,4R*)-3- 0.62 491(azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide 1.106rac-5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3-0.58 477.1 (azetidine-1-carbonyl)-1-cyclopentyl-piperidin-4-yl]-amide1.107 rac-5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid[(3R*,4R*)-3- 0.57 463.3(azetidine-1-carbonyl)-1-cyclopropylmethyl-piperidin-4-yl]-amide 1.1085-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3-0.62 491.3(azetidine-1-carbonyl)-1-((1RS,2RS)-2-methyl-cyclopentyl)-piperidin-4-yl]-amide (mixture of isomers) 1.109rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.6 505[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-amide 1.110rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 1.1491.3 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid(2- methoxy-1,1-dimethyl-ethyl)-amide 1.111rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.71 537.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide 1.111a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.71537.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 1) 1.111b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.71537.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 2) 1.112rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.68 523 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide 1.113rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.67509 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy- 1,1-dimethyl-ethyl)-amide 1.113a(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.67 509.1 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 1) 1.113b(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.67 509.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 2) 1.114(3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro- 0.7537 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(2- methoxy-1,1-dimethyl-ethyl)-amide (mixture of isomers) 1.115rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.69519 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide 1.116rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.67 505.3 carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide 1.117(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.54 538.2 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.117a(3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.54 538.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide or(3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (2^(nd) eluted enantiomer) 1.118(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.5 524.2 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.118a(3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.51 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide or(3R,4R)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (2^(nd) eluted enantiomer) 1.119(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.49 510.1[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.120(3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-0.53 538.2amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.121(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.63556.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.121a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.61556.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 1) 1.121b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.63556.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 2) 1.122(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6542.3 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.122a(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.58542.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 1) 1.122b(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6542.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 2) 1.123(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.57 528.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.123a(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.58 528 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide or(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin- 2-yl-ethyl)-amide (2^(nd) eluted enantiomer) 1.124(3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-0.62 556.1 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1- pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.125(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-0.61 538.2 amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.125a(3S,4S)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-0.62 538.2 amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)-amide or(3R,4R)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide(2^(nd) eluted enantiomer) 1.126(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.58524.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.127(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-1 539.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.128(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-1 525.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.129(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6557.2 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.129a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6557.4 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (enantiomer 1) 1.129b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.63557.2 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (enantiomer 2) 1.130(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.59543.3 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.131(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.59 529 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.132(3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-0.62 557.3 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1- pyrazin-2-yl-ethyl)-amide (mixture of isomers) 1.133(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-0.59 539.3 amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)-amide (mixture of isomers) 1.134(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.69 515.4 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.135(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.66 501.4 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.136(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.64 487.3[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.137(3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-0.68 515.4amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.138(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.74519.3 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.138a(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.73519.2 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (enantiomer 1) 1.138b(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.74519.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (enantiomer 2) 1.139(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.72 505.3 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.139a(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.71 505.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (enantiomer 1) 1.139b(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.73 505.3 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (enantiomer 2) 1.140(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-0.75 515.4 amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.141(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.73501.3 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.142rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-0.64 568.2 4-carbonyl]-amino}-piperidine-3-carboxylic acid[1-(5-fluoro-pyridin-2-yl)- cyclopropyl]-amide 1.143rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.72 586.1 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(5-fluoro-pyridin-2-yl)- cyclopropyl]-amide 1.144rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.68558.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid[1-(5-fluoro- pyridin-2-yl)-cyclopropyl]-amide 1.145(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.72 549.4 carbonyl]-amino}-piperidine-3-carboxylic acid((1R*,2S*)-2-phenyl- cyclopropyl)-amide and(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.146(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.69 535.3 carbonyl]-amino}-piperidine-3-carboxylic acid((1S*,2R*)-2-phenyl- cyclopropyl)-amide and(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R*,2S*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.147(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-0.77 549.4 amino}-piperidine-3-carboxylic acid((1S*,2R*)-2-phenyl-cyclopropyl)- amide and(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbony]-amino}-piperidine-3-carboxylic acid ((1R*,2S*)-2-phenyl-cyclopropyl)-amide(mixture of isomers) 1.148(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.75535.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide and (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic acid((1R*,2S*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.149rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-0.56 433.2 5-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide1.150(3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1-0.61 461.3 ((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 1.151rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-0.65 491.3 5-carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide 1.152rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-0.65 520.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl- ethyl)-amide 1.153rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.61492.3 [1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(2- methoxy-1,1-dimethyl-ethyl)-amide 1.154(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.57 510 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.154a(3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.58 510 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide or(3R,4R)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin- 2-yl-ethyl)-amide (2^(nd) eluted enantiomer) 1.155(3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1-0.61 538.2 ((1RS,2RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid((R)-1- pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.156(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-0.56 539.2 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.156a(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-0.57 539.2 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide or(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1- pyridin-2-yl-ethyl)-amide (2^(nd) eluted enantiomer) 1.157(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-0.53 525.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.158(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.52 511.1[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1- pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.159(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.55 510.9 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.160(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-0.56 540.4 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.161(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.71 487.3 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.162(3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1-0.74 515.4 ((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid((R)-1- cyclobutyl-ethyl)-amide (mixture of isomers) 1.163rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-0.66 540.3 5-carbonyl]-amino}-piperidine-3-carboxylic acid[1-(5-fluoro-pyridin-2-yl)- cyclopropyl]-amide 1.164(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.73 521.3 carbonyl]-amino}-piperidine-3-carboxylic acid((1S*,2R*)-2-phenyl- cyclopropyl)-amide and(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R*,2S*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.165rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-0.55 550.2 4-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl- cyclopropyl)-amide 1.165a(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.54 550.2 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 1) 1.165b(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.55 550.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 2) 1.166rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.51 536.1[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin- 2-yl-cyclopropyl)-amide 1.167rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.5522 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin- 2-yl-cyclopropyl)-amide 1.168(3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-0.54 550.2amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)-amide (mixture of isomers) 1.169rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.65 568.3 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 1.170rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.6 554.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 1.170a(3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6554.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide or(3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide (1^(st) eluted enantiomer) 1.171rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.59540.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl- cyclopropyl)-amide 1.171a(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.58 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 1) 1.171b(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.59 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 2) 1.172(3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-0.62 568.1 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1- pyridin-2-yl-cyclopropyl)-amide (mixture of isomers) 1.173rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.59 536.3 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 1.174rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-0.57 522.1 5-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl- cyclopropyl)-amide 1.175(3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbony]-amino}-1-0.61 550.2 ((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid(1-pyridin- 2-yl-cyclopropyl)-amide (mixture of isomers) 1.176rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.62 555.3 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 1.176a(3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.61555.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide or (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (2^(nd) eluted enantiomer) 1.177rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.63541.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide 1.178rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-0.61 523.1 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 1.179(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.61 523 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrazin-2-yl-cyclopropyl)-amide 1.180(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.56 523 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridazin-3-yl- cyclopropyl)-amide 1.181(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.62 537.1 amino}-piperidine-3-carboxylic acid(1-pyrazin-2-yl-cyclopropyl)-amide 1.182(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.57 537.1 amino}-piperidine-3-carboxylic acid(1-pyridazin-3-yl-cyclopropyl)-amide 1.183rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65500.3 carbonyl]-amino}-piperidine-3-carboxylic acid(cyano-dimethyl-methyl)- amide 1.184(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.71 565.4 amino}-piperidine-3-carboxylic acid[1-(4,6-dimethyl-pyrimidin-2-yl)- cyclopropyl]-amide 1.185(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7551.4 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(4,6-dimethyl-pyrimidin- 2-yl)-cyclopropyl]-amide 1.186(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 461.3 amino}-piperidine-3-carboxylic acid dimethylamide 1.187a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 538.4 amino}-piperidine-3-carboxylic acid((S)-1-pyridin-2-yl-ethyl)-amide (enantiomer 1) 1.187b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 538.3 amino}-piperidine-3-carboxylic acid((S)-1-pyridin-2-yl-ethyl)-amide (enantiomer 2) 1.187c(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 538.3 amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)-amide (enantiomer 1) 1.187d(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.62 538.2 amino}-piperidine-3-carboxylic acid((R)-1-pyridin-2-yl-ethyl)-amide (enantiomer 2) 1.188a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 552.2 amino}-piperidine-3-carboxylic acid[(R)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 1) 1.188b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.59 552.2 amino}-piperidine-3-carboxylic acid[(R)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 2) 1.188c(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 552.2 amino}-piperidine-3-carboxylic acid[(S)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 1) 1.188.d(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.59 552.2 amino}-piperidine-3-carboxylic acid[(S)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 2) 1.189rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-0.70 555 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 1.189a(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-0.70 555.3 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide or(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (1^(st) eluted enantiomer) 1.190rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)- 0.7555.2 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide 1.191rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-0.6 523.4 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 1.192rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)- 0.70555.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide 1.192a(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)- 0.70555.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide (enantiomer 1) 1.192b(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)- 0.70555.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide (enantiomer 2) 1.193rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)- 0.70555 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide 1.193a(3R,4R)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)-isoxazole-0.70 555.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide or(3S,4S)-1-cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (2^(nd) elutedenantiomer) 1.194a(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-0.60 541 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide or(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (1st eluted enantiomer) 1.195rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)-0.60 535.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide 1.196rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole-0.50 506 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 1.197rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-0.6 536.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl- cyclobutyl)-amide 1.198rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-0.8 551.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid[1-(2-methoxy-phenyl)- cyclopropyl]-amide 1.199rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3-difluoro-phenyl)-isoxazole-0.6 523.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide

General Method B for the Synthesis of Compounds of Formula (I) BuildingsBlocks Preparation of Building Blocks of Structure B-6

BB 2.01:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide 2.01a:rac-(3R*,4R*)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

To a solution of rac-(3R*,4R*)-4-amino-1-benzyl-piperidine-3-carboxylicacid methyl ester (10.00 g, 33.4 mmol) in DMF (200 mL) is added5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (7.74 g, 33.4 mmol).DIPEA (24.5 mL, 140 mmol) is then added followed by HATU (13.32 g, 35mmol). The reaction mixture is stirred for 1 h. The reaction mixture isconcentrated, diluted with DCM (750 mL) and treated with aq. sat. NaHCO₃(600 mL). The organic layer is dried over MgSO₄ and evaporated. Thecrude residue is purified by prep. LC-MS in basic conditions to give thetitle compound; LC-MS method D t_(R)=1.14 min; [M+H]⁺=456.18.

2.01b:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

To a solution ofrac-(3R*,4R*)-1-benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester 2.01a (11.33 g, 24.9 mmol) in ethyl acetate (250 mL)under argon is added 10% wet palladium on activated charcoal (2.647,2.49 mmol) and di-tert-butyl-dicarbonate (6.03 g, 27.4 mmol). Afterdegassing the reaction flask, the mixture is hydrogenated for 5 h at RT.The catalyst is filtered, washed with EtOAc and the solvent isevaporated. The crude residue is purified by prep. LC-MS with basicconditions to give the title compound; LC-MS method D t_(R)=1.11 min;[M+H]⁺=465.90.

2.01c:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester 2.01b (8.71 g, 18.7 mmol) isdissolved in THF (114 mL). Aq. 1M NaOH solution (56.1 mL, 56.1 mmol) isthen added and the mixture stirred at RT for 3 h. The reaction mixtureis acidified to around pH=3 with 2M aq. HCl solution (30 mL) andconcentrated. The resulting suspension is filtered, washed twice withwater (2×14 mL) and dried under HV. The title compound is obtained as awhite powder; LC-MS method D t_(R)=0.66 min; [M+H]⁺=452.17.

2.01d:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-piperidine-1-carboxylicacid tert-butyl ester

To a solution ofrac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 2.01c (5 g, 11 mmol) in DMF (58 mL) at RT isadded a 2M solution of dimethylamine in THF (22 mL, 44 mmol). DIPEA(6.15 mL, 35.2 mmol) is then added followed by HATU (4.4 g, 11.6 mmol).The reaction mixture is stirred at RT for 4 h. The volatiles areevaporated and the crude mixture is purified by prep. LC-MS with basicconditions to give the title compound; LC-MS method D t_(R)=1.01 min;[M+H]⁺=479.23.

2.01:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide

rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-piperidine-1-carboxylicacid tert-butyl ester 2.01d (4.53 g, 9.47 mmol) is dissolved in MeOH(47.3 mL) at RT. A 4M solution of HCl in dioxane (47.3 mL, 189 mmol) isadded and the reaction mixture is stirred at RT for 1 h. The solventsare evaporated to give the title compound; LC-MS method D t_(R)=0.75min; [M+H]⁺=379.11.

Preparation of Building-Blocks of General Formula (B-6) Used asIntermediates in the Preparation of Examples 2.001 to 2.108

The following intermediates are prepared in analogy to BB 2.01:

BB 2.02:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide hydrochloride 2.02b:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(methyl-phenethyl-carbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from building block 2.01c and N-methyl-2-phenylethylamine;LC-MS method D: t_(R)=1.17 min; [M+H]⁺=569.14.

2.02:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide hydrochloride

The title compound is prepared according to the procedure 2.01, startingfrom building block 2.02b; LC-MS method D: t_(R)=0.92 min;[M+H]⁺=469.18.

BB 2.03:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-ethyl)-amide hydrochloride 2.03b:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from building block 2.01c and 1-(2-pyridyl)ethylamine; LC-MSmethod D: t_(R)=1.01 min; [M+H]⁺=556.13.

2.03:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-ethyl)-amide hydrochloride

The title compound is prepared according to the procedure 2.01, startingfrom building block 2.03b; LC-MS method D: t_(R)=0.77 min;[M+H]⁺=456.09.

BB 2.04:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide hydrochloride 2.04a:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

The title compound is prepared by chiral preparative HPLC ofrac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester using a column ChiralPak IC, 5μm, 20×250 mm; with a mixture of A (25% Hept) and B (75% EtOH, 0.1% DEA)as eluent and a flow of 34 mL/min. Chiral HPLC: t_(R)=7.3 min.

2.04b:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

The title compound is prepared according to the procedure 2.01c,starting from building block 2.04a; LC-MS method A: t_(R)=0.77 min;[M+H]⁺=452.04.

2.04c:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from 2.04b and 1-(pyrimidin-2-yl)cyclopropan-1-aminehydrochloride; LC-MS method A: t_(R)=0.94 min; [M+H]⁺=569.19.

2.04:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide hydrochloride

The title compound is prepared according to the procedure 2.01 describedabove, starting from building block 2.04c; LC-MS method A: t_(R)=0.62min; [M+H]⁺=469.23.

BB 2.05:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide hydrochloride 2.05a:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

The title compound is prepared by chiral preparative HPLC ofrac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester using a column_ChiralPak IC, 5μm, 20×250 mm; with a mixture of A (25% Hept) and B (75% EtOH, 0.1% DEA)as eluent and a flow of 34 mL/min. Chiral HPLC: t_(R)=5.9 min.

2.05b:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

The title compound is prepared according to the procedure 2.01c,starting from building block 2.05a; LC-MS method D: t_(R)=0.62 min;[M+H]⁺=452.17.

2.05c:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from 2.05b and dimethylamine solution 2 M in THF; LC-MS methodD: t_(R)=1.00 min; [M+H]⁺=479.16.

2.05:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide hydrochloride

The title compound is prepared according to the procedure 2.01 describedabove, starting from building block 2.05c; LC-MS method D: t_(R)=0.75min; [M+H]⁺=379.15.

BB 2.06:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(1-oxy-pyridin-2-yl)-ethyl]-amide hydrochloride 2.06b:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from building block 2.01c and (R)-1-(pyridin-2-yl)ethanamine;LC-MS method A: t_(R)=0.87 min; [M+H]⁺=556.26.

2.06c:2-((R)-14(3R*,4R*)-1-(tert-butoxycarbonyl)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)ethyl)pyridine-1-oxide

To a solution of 2.06b (90 mg, 0.162 mmol) in DCM (3 mL) at 0° C. isadded portionwise 3-chloroperbenzoic acid (47.2 mg, 0.211 mmol). Thereaction mixture is stirred at RT for 1 h. The mixture is diluted withDCM and washed with aq. sat. NaHCO₃. The org phase is dried over MgSO₄,filtered and concentrated to give the tittle compound as a white powder;LC-MS method A: t_(R)=0.96 min; [M+H]⁺=572.28.

2.06:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(1-oxy-pyridin-2-yl)-ethyl]amide hydrochloride

The title compound is prepared according to the procedure 2.01, startingfrom building block 2.06c; LC-MS method A: t_(R)=0.63 min;[M+H]⁺=472.19.

BB 2.07:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide hydrochloride 2.07b:rac-tert-butyl(3R*,4R*)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)-34(1-(Pyridin-2-yl)cyclopropyl)carbamoyl)piperidine-1-carboxylate

The title compound is prepared according to the procedure 2.01d,starting from building block 2.01c and1-(pyridin-2-yl)cyclopropan-1-amine; LC-MS method A: t_(R)=0.88 min;[M+H]⁺=568.26.

2.07c:rac-2-(14(3R*,4R*)-1-(tert-butoxycarbonyl)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)cyclopropyl)pyridine1-oxide

The title compound is prepared according to the procedure 2.06c,starting from building block 2.07b; LC-MS method A: t_(R)=0.91 min;[M+H]⁺=584.27.

2.07:(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide hydrochloride

The title compound is prepared according to the procedure 2.01, startingfrom building block 2.07c; LC-MS method A: t_(R)=0.63 min;[M+H]⁺=484.19.

BB 2.08:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide hydrochloride 2.08b:tert-butyl(3S,4S)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)-3-((1-(pyridin-2-yl)cyclopropyl)carbamoyl)piperidine-1-carboxylate

The title compound is prepared according to the procedure 2.01d,starting from building block 2.04b and1-(pyridin-2-yl)cyclopropan-1-amine; LC-MS method A: t_(R)=0.82 min;[M+H]⁺=568.02.

2.08c:2-(1-((3S,4S)-1-(tert-butoxycarbonyl)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)cyclopropyl)pyridine1-oxide

The title compound is prepared according to the procedure 2.06c,starting from building block 2.08b; LC-MS method A: t_(R)=0.87 min;[M+H]⁺=583.99.

2.08:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide hydrochloride

The title compound is prepared according to the procedure 2.01, startingfrom building block 2.08c; LC-MS method A: t_(R)=0.58 min;[M+H]⁺=484.06.

BB 2.09:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-cyano-cyclobutyl)-amide hydrochloride 2.09b:rac-(3R*,4R*)-3-(1-Cyano-cyclobutylcarbamoyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from building block 2.01c and 1amino-cyclobutane carbonitrile;LC-MS method A: t_(R)=1.03 min; [M+H]⁺=550.02.

2.09:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-cyano-cyclobutyl)-amide hydrochloride

The title compound is prepared according to the procedure 2.01, startingfrom building block 2.09b; LC-MS method A: t_(R)=0.70 min; [M+H]⁺=430.2.

BB 2.10:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide hydrochloride 2.10c:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from 2.05b and 1-(pyrimidin-2-yl)cyclopropan-1-aminehydrochloride; LC-MS method A: t_(R)=0.86 min; [M+H]⁺=569.19.

2.10:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide hydrochloride

The title compound is prepared according to the procedure 2.01 describedabove, starting from building block 2.10c; LC-MS method A: t_(R)=0.61min; [M+H]⁺=469.19.

BB 2.11:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl-methyl-amide hydrochloride 2.11c:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(ethyl-methyl-carbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from 2.05b and N-ethylmethylamine; LC-MS method A: t_(R)=0.99min; [M+H]⁺=493.18.

2.11:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl-methyl-amide hydrochloride

The title compound is prepared according to the procedure 2.01 describedabove, starting from building block 2.11c; LC-MS method A: t_(R)=0.69min; [M+H]⁺=393.18.

BB 2.12:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-(2-pyridin-2-yl-ethyl)-amide hydrochloride 2.12c:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from 2.05b and N-methyl-2-(pyridin-2-yl)ethan-1-amine; LC-MSmethod A: t_(R)=0.78 min; [M+H]⁺=570.17.

2.12:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-(2-pyridin-2-yl-ethyl)-amide hydrochloride

The title compound is prepared according to the procedure 2.01 describedabove, starting from building block 2.12c; LC-MS method A: t_(R)=0.57min; [M+H]⁺=470.18.

BB 2.13:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-pyridin-2-yl-ethyl)-amide hydrochloride 2.13c:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(2-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from 2.05b and 2-(pyridin-2-yl)ethan-1-amine; LC-MS method A:t_(R)=0.76 min; [M+H]⁺=557.15.

2.13:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-pyridin-2-yl-ethyl)-amide hydrochloride

The title compound is prepared according to the procedure 2.01 describedabove, starting from building block 2.12c; LC-MS method A: t_(R)=0.56min; [M+H]⁺=456.18.

BB 2.14:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.14a:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-ten-butyl ester 3-ethyl ester

To a solution of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester 4.06c (3.7 g, 13.6 mmol) in DMF (100mL) is added 5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carboxylicacid sodium salt (3.73 g, 14.1 mmol). TEA (7.56 mL, 54.3 mmol) is thenadded followed by HATU (6.2 g, 16.3 mmol). The reaction mixture isstirred for 1 h. The reaction mixture is concentrated, diluted with DCM(250 mL) and treated with aq. sat. NaHCO₃ (250 mL). The organic layer isdried over MgSO₄ and evaporated. The crude residue is purified by flashchromatography using n-heptan/EtOAc 3:1 as eluent to deliver(3R,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester as a white powder. This compoundis dissolved in EtOH (40 mL) and EtOAc (20 mL). Sodium ethoxide 95%powder (3.44 g, 48 mmol) is added at once to and the resulting mixtureis stirred under an argon atmosphere at RT for 4 d. The reaction mixtureis quenched with sat. aq. NH₄Cl (100 mL) and extracted thrice with DCM(3×100 mL). The combined organic extracts are dried over MgSO₄, filteredand concentrated in vacuo. The crude is purified by prep-LC-MS, underbasic conditions (method E) followed by chiral preparative SFC in orderto remove traces of the [R,R]-isomer (Column: Regis (R,R) Whelk-O1,30×250 mm, 5 μm or ChiralPak IC, 30×250 mm, 5 μm; eluent: mixture of A(65% CO₂), and B (35% of DCM/EtOH/DEA 50:50:0.1), flow 160 mL/min.t_(R)=1.18 min.) The title product is obtained as a white powder; LC-MSmethod A: t_(R)=1.07 min; [M+H]⁺=496.96.

2.14b:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)1,3,4-thiadiazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

The title compound is obtained by treatment of(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester with sodium hydroxide followed byHCl according to procedure 2.01c; LC-MS method A: t_(R)=0.94 min;[M+H]⁺=468.88.

2.14c:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from 2.14b and 1-(pyrimidin-2-yl)cyclopropan-1-aminehydrochloride; LC-MS method D: t_(R)=0.94 min; [M+H]⁺=585.34.

2.14:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

The title compound is prepared according to the procedure 2.01 describedabove, starting from building block 2.14c; LC-MS method A: t_(R)=0.67min; [M+H]⁺=486.24

General Procedures for the Preparation of Examples 2.001 to 2.109 MethodD:

To a solution of the respective amine (BB 2.01 to BB 2.14) (0.1 mmol) inDCM (mL) is added a commercially available aldehyde or ketone (0.12 to 1mmol) followed by sodium triacetoxyborohydride (0.13 to 0.4 mmol). Thereaction mixture is stirred overnight at RT. The reaction mixture isthen diluted with DCM or chloroform (3 mL) and treated with aq. sat.NaHCO₃ (2 mL). The organic phase is dried over Na₂SO₄, filtered and thesolvent is evaporated. The crude residue is purified by prep. LC-MSusing method E.

Method E:

To a solution of the respective amine (BB 2.01 to BB 2.14) (0.1 mmol) inDMF (mL) is added a commercially available aldehyde or ketone (0.2 to 1mmol) followed by sodium triacetoxyborohydride (0.23 mmol). The reactionmixture is stirred overnight at RT. 150 μL water are added and theproduct is purified by prep. LC-MS using method E.

Method F:

To the respective amine (BB 2.01 to BB 2.14) (0.5 mmol) and acommercially available ketone (0.6 mmol) and titanium(IV) isopropoxide(1 mmol) are stirred under argon at 80° C. for 4.5 h. Methanol (1.18 mL)is added followed by sodium borohydride (1.5 mmol) in one portion. Thereaction mixture is stirred at RT for 1 h. Water (1.2 mL) is added. Theresulting suspension is filtered, washed with 9 mL DCM/MeOH 3/1 and thesolvents are evaporated. The crude residue is purified by prep. LC-MSusing method E.

Method G:

The respective amine (BB 2.01 to BB 2.14) (0.1 mmol) is dissolved inwater (0.7 mL). DIPEA (0.3 mmol) is added followed by a commerciallyavailable epoxide (0.4 mmol). The reaction mixture is stirred at 100° C.for 17 h. The solvent is evaporated and the crude mixture is dissolvedin 1 mL MeOH/DMF and purified by prep. LC-MS using method E.

Method H:

To an ice cold solution of the respective amine (BB 2.01 to BB 2.14)(0.1 mmol) and K₂CO₃ (0.2 mmol) in acetone (5 mL) is added acommercially available alkyl bromide (0.11 mmol). The mixture is stirred18 h at RT. Another equivalent of alkyl bromide is added and the mixtureis stirred 18 h at 50° C. The reaction mixture is filtered and thesolvent is evaporated under reduced pressure. The residue is purified byPrep HPLC using method E.

Example 2.001rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid dimethylamide

To a solution ofrac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide (BB 2.01) (41.5 mg, 0.1 mmol) in DCM (0.5 mL) isadded acetone (27.8 mg, 0.036 mL, 0.48 mmol) followed by sodiumtriacetoxyborohydride (61 mg, 0.27 mmol). The reaction mixture isstirred overnight at RT. The reaction mixture is then diluted withchloroform (3 mL) and treated with aq. sat. NaHCO₃ (2 mL). The organicphase is dried over Na₂SO₄, filtered and the solvent is evaporated. Thecrude residue is purified by prep. LC-MS using method E. LC-MS QCmethod: t_(R)=0.56 min; [M+H]⁺=421.1.

Compounds of Examples 2.001 to 2.108 listed in Table 2 below areprepared by applying one of the above-mentioned general procedures D, E,F, G, or H to the building blocks BB-2.01 BB-2.14 or BB-8.01-BB-8.02coupled with commercially available aldehydes, ketones, alkylhalogenides or epoxydes.

Enantiomerically pure compounds are obtained by using one of the abovementioned preparative chiral chromatography methods.

TABLE 2 Examples 2.001-2.108 QC LC-MS Mass Example Found Nr SubstanceName t_(R) (min) [M + H]⁺ 2.001rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.56 421.1 1-isopropyl-piperidine-3-carboxylic acid dimethylamide 2.002rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.54 407.3 1-ethyl-piperidine-3-carboxylic acid dimethylamide 2.003rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.75 511 1-isopropyl-piperidine-3-carboxylic acid methyl-phenethyl-amide2.004rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.73 497.3 1-ethyl-piperidine-3-carboxylic acid methyl-phenethyl-amide2.005rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.78 537.4 carbonyl]-amino}-piperidine-3-carboxylic acidmethyl-phenethyl-amide 2.006rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.77523.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl-phenethyl-amide 2.007(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.57 498 isopropyl-piperidine-3-carboxylic acid((1RS)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 2.008(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.55 484.1 ethyl-piperidine-3-carboxylic acid((1RS)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 2.009(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.59524.5 carbonyl]-amino}-piperidine-3-carboxylic acid((1RS)-1-pyridin-2-yl- ethyl)-amide (mixture of isomers) 2.010(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.58 510.1 carbonyl]-amino}-piperidine-3-carboxylic acid((1RS)-1-pyridin-2-yl- ethyl)-amide (mixture of isomers) 2.011(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.55 525.9 carbonyl]-amino}-piperidine-3-carboxylic acid[(R)-1-(1-oxy-pyridin-2- yl)-ethyl]-amide (mixture of isomers) 2.013(3R*,4R*)-1-((1RS)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-0.61 447.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.014(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.58 477.3((1RS,2RS)-2-hydroxymethyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.015(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.68 475.3 ((1RS,2RS)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.016(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.61 447.3 ((1RS,2RS)-2-methyl-cyclobutyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.016a(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.61447.3 ((1RS,2RS)-2-methyl-cyclobutyl)-piperidine-3-carboxylic aciddimethylamide, mixture of isomers 1 2.016b(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.6447.3 ((1RS,2RS)-2-methyl-cyclobutyl)-piperidine-3-carboxylic aciddimethylamide, mixture of isomers 2 2.017(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}- 0.65461.1 (1RS)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.018(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.67 475.3 ((1RS)-3,3-dimethyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.019rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.59 447.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide2.019a (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.59 447.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamideor(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (1^(st) elutedenantiomer) 2.020rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.65 449.1 1-(2,2-dimethyl-propyl)-piperidine-3-carboxylic aciddimethylamide 2.021rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.64 449 1-(3-methyl-butyl)-piperidine-3-carboxylic acid dimethylamide2.022rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.68 463.4 1-(3,3-dimethyl-butyl)-piperidine-3-carboxylic aciddimethylamide 2.023(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.63 461.3 ((1RS,2RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.023a(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.63461.3 ((1RS,RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide, mixture of isomere 1 2.023b(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.63461.3 ((1RS,RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic aciddimethylamide, mixture of isomers 2 2.024(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.72 489.3 ((1RS)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.025rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.66 473.3 1-spiro[3.3]hept-2-yl-piperidine-3-carboxylic aciddimethylamide 2.026(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.61 479.3 ((1RS,4RS)-4-fluoro-cyclohexyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.027rac-(3R*,4R*)-1-(4,4-Difluoro-cyclohexyl)-4-{[5-(2,4-difluoro-phenyl)-0.63 497.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide 2.028rac-(3R*,4R*)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.56433.4 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.029rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.58 433isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide2.030 rac-(3R*,4R*)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-0.66 461.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide 2.031rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.64 461.3 1-(3,3-dimethyl-cyclobutyl)-piperidine-3-carboxylic aciddimethylamide 2.032(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.67 491 ((1RS,3RS)-3-methoxy-cyclohexyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.033(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.67 491 ((1RS,2RS)-2-methoxy-cyclohexyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.034rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.63 447.3 1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic aciddimethylamide 2.035rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.67 461 1-(1-methyl-cyclobutylmethyl)-piperidine-3-carboxylic aciddimethylamide 2.036rac-(3R*,4R*)-1-Cyclopent-1-enylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.66459.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide 2.037(3R*,4R*)-(1RS,2RS,4RS)-1-Bicyclo[2.2.1]hept-2-yl-4-{[5-(2,4-difluoro-0.64 473.3 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide (mixture of isomers) 2.038rac-(3R*,4R*)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-0.62 447.3 3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide2.039 rac-(3R*,4R*)-1-(2-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-0.62 447.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide 2.040(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.63 479.3 ((1RS,2RS)-2-fluoro-cyclohexyl)-piperidine-3-carboxylic aciddimethyl amide (mixture of isomers) 2.045(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.58 433.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide2.046 (3R,4R)-1-((1RS)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-0.62 447.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.047(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}- 0.68473 (1RS)-1-spiro[2.4]hept-4-yl-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.048(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.61 477.3 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic aciddimethylamide (mixture of isomers) 2.049(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.56 451 ((1RS,2RS)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid dimethylamide (mixture of isomers) 2.050(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.79 567.4 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acidmethyl- phenethyl-amide (mixture of isomers) 2.051(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.75 541 ((1RS,2RS)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide (mixture of isomers) 2.052rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.72 513 1-(2-hydroxy-ethyl)-piperidine-3-carboxylic acidmethyl-phenethyl- amide 2.053(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.59 554.2 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid((1RS)- 1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 2.054(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.57 528 ((1RS,2RS)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid ((1RS)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 2.055(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-0.6 527.1 methoxy-ethyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.056(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.58497 ethyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 2.057(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.58502.2 ((1,1,2,2,2-d₅-ethyl)-piperidine)-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 2.058rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.71 469 (BB 2.02) piperidine-3-carboxylic acid methyl-phenethyl-amide2.059 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.58 469.27 (BB 2.04) piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 2.060(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-0.60 567 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid(1- pyrimidin-2-yl-cyclopropyl)-amide (mixture of stereoisomers) 2.061rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.60538.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid[1-(1-oxy- pyridin-2-yl)-cyclopropyl]-amide 2.062rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.65 552.2 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(1-oxy-pyridin-2-yl)- cyclopropyl]-amide 2.062a(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65552.2 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(1-oxy-pyridin-2-yl)- cyclopropyl]-amide (Enantiomer 1) 2.062b(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65552.17 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(1-oxy-pyridin-2-yl)- cyclopropyl]-amide (Enantiomer 2) 2.063(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.60 538.4 amino}-piperidine-3-carboxylic acid[1-(1-oxy-pyridin-2-yl)-cyclopropyl]- amide 2.064rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.60 498 carbonyl]-amino}-piperidine-3-carboxylic acid(1-cyano-cyclobutyl)- amide 2.065(3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.70 551 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 2.066(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60537.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.067(3S,4S)-1-(1-Difluoromethyl-cyclopropylmethyl)-4-{[5-(2,4-difluoro- 0.60573 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1- pyrimidin-2-yl-cyclopropyl)-amide 2.068(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(4-0.70 577 fluoro-benzyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.069(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.70539.1 (2,2-dimethyl-propyl)-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 2.070(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.60525.2 isobutyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.071(3S,4S)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.70559.1 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.072(3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60537.4 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.073(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.60511.2 isopropyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.074(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.60 523.1 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.075(3S,4S)-1-Cyclopropyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60509.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.076(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60461.3 carbonyl]-amino}-piperidine-3-carboxylic acid ethyl-methyl-amide2.077(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.60 447 carbonyl]-amino}-piperidine-3-carboxylic acidethyl-methyl-amide 2.078(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.50538.1 carbonyl]-amino}-piperidine-3-carboxylic acidmethyl-(2-pyridin-2-yl- ethyl)-amide 2.079(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.50 524 carbonyl]-amino}-piperidine-3-carboxylic acidmethyl-(2-pyridin-2-yl- ethyl)-amide 2.080(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.50 510.2 carbonyl]-amino}-piperidine-3-carboxylic acid(2-pyridin-2-yl-ethyl)- amide 2.081(3R,4R)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.70469.3 amino}-piperidine-3-carboxylic acid dimethylamide 2.082(3R,4R)-1-(2-Chloro-benzyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.70 503.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide2.083(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-0.70 487.3 fluoro-benzyl)-piperidine-3-carboxylic acid dimethylamide2.084(3S,4S)-1-((1RS)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-0.60 559.1 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1- pyrimidin-2-yl-cyclopropyl)-amide (mixture of isomers) 2.085(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-0.60 472.4 methyl-1H-pyrrol-3-ylmethyl)-piperidine-3-carboxylic aciddimethylamide 2.086(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.60483.4 methyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 2.087(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3-0.60 529 fluoro-propyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.088rac-(3R*,4R*)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60523 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.089(3S,4S)-1-(3,3-Difluoro-cyclobutyl)-4-{[5-(2,4-difluoro-phenyl)- 0.7 559isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.090(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-0.6 537.1 methyl-cyclopropylmethyl)-piperidine-3-carboxylic acid(1-pyrimidin-2- yl-cyclopropyl)-amide 2.091(3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.5 522[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide 2.092(3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-0.5 536.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide 2.093(3S,4S)-1-Allyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6509.2 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.094(3S,4S)-1-Bicyclo[3.1.0]hex-3-yl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.6 549.2 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 2.095(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.5511.2 propyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 2.096(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}- 0.6 469(BB 8.02) piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 2.097(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-0.6 523.1 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.098(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-0.6 537.1 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.099(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-1- 0.6511.4 isopropyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.100(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-1-(1- 0.6541.3 fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 2.101(3S,4S)-1-(3,3-Difluoro-cyclobutylmethyl)-4-{[5-(2,4-difluoro-phenyl)-0.6 573 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin- 2-yl-cyclopropyl)-amide 2.102(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.6541 thietan-3-yl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.103(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.6549 spiro[2.3]hex-5-yl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.104(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]- 1.0486.4 (BB 2.14) amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 2.105(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-0.6 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 2.106(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]- 0.6558.1 amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid(1- pyrimidin-2-yl-cyclopropyl)-amide 2.107(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]- 0.6514.1 amino}-1-ethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.108(3S,4S)-1-(Cyclopropyl-(d₂-methyl))-4-{[5-(2,4-difluoro-phenyl)- 0.6525.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin- 2-yl-cyclopropyl)-amide

General Method C for the Synthesis of Compounds of Formula (I) BuildingsBlocks Preparation of Building Blocks of Structure C-3

BB 3.01: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic aciddimethylamide 3.01a:rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylicacid

rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylicacid methyl ester 1.01a (2.85 g, 7.35 mmol) is dissolved in THF (45 mL)at RT. Aq. 1M NaOH solution (22.1 mL, 22.1 mmol) is then added and themixture stirred at RT for 72 h. The reaction mixture is acidified toaround pH=3 with a 2M HCl solution (12 mL) and evaporated. The resultingsuspension is dissolved with DCM, the organic phase is dried over MgSO₄and the solvents are evaporated to give the title compound; LC-MS methodD t_(R)=0.54 min; [M+H]⁺=327.23.

3.01b:rac-((3R*,4R*)-1-Cyclohexyl-3-dimethylcarbamoyl-piperidin-4-yl)-carbamicacid tert-butyl ester

To a solution ofrac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylicacid 3.01a (2.4 g, 7.35 mmol) in DMF (36.8 mL) is added a 40% solutionof dimethylamine in water (2.79 mL, 22.1 mmol). DIPEA (4.11 mL, 23.5mmol) is then added followed by HATU (2.93 g, 7.72 mmol). The reactionmixture is stirred for 2 h. The reaction mixture is concentrated,dissolved in DCM (150 mL) and treated with aq. sat. NaHCO₃(150 mL). Theorganic layer is separated and the aq. phase is further extracted withDCM (3×150 mL). The combined organic phases are dried over MgSO₄ andevaporated. The crude residue is purified by prep. LC-MS with basicconditions (method E). The title compound is obtained; LC-MS method Dt_(R)=0.91 min; [M+H]⁺=353.96.

3.01: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic aciddimethylamide

rac-((3R*,4R*)-1-Cyclohexyl-3-dimethylcarbamoyl-piperidin-4-yl)-carbamicacid tert-butyl ester (2.08 g, 5.88 mmol) is dissolved in MeOH (29.5 mL)at RT. A 4M solution of HCl in dioxane (29.5 mL, 118 mmol) is added andthe reaction is stirred at RT for 1 h. The reaction mixture isconcentrated, dissolved in DCM (150 mL) and treated with aq. sat. NaHCO₃(50 mL). The organic layer is separated and the aq. phase is extractedtwice with DCM (2×100 mL) and twice with chloroform (2×100 mL). Thecombined organic phases are dried over MgSO₄, filtered and the solventis evaporated to give the crude title compound; LC-MS method Dt_(R)=0.68 min; [M+H]⁺=254.24.

Preparation of Building-Blocks of General Formula (C-3) Used asIntermediates in the Preparation of Examples 3.001 to 3.022

The following intermediates are prepared in analogy to BB 3.01:

BB 3.02: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)-amide, dihydrochloride 3.02b:rac-[(3R*,4R*)-1-Cyclohexyl-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

The title compound is prepared according to the procedure 3.01b,starting from building block 3.01a and 1-(2-pyridyl)cyclopropylaminedihydrochloride; LC-MS method D: t_(R)=0.97 min; [m+H]⁺=443.21.

3.02: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)-amide, dihydrochloride

The title compound is prepared according to the procedure 3.01, startingfrom building block 3.02b; LC-MS method D: t_(R)=0.77 min;[M+H]⁺=343.17.

BB 3.03: rac-(3R*,4R*)-4-Amino-1-cyclopentyl-piperidine-3-carboxylicacid dimethylamide 3.03a:rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopentyl-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 3.01a,starting from building block 1.03a; LC-MS method D: t_(R)=0.51 min;[M+H]⁺=313.08.

3.03b:rac-((3R*,4R*)-1-Cyclopentyl-3-dimethylcarbamoyl-piperidin-4-yl)-carbamicacid tert-butyl ester

The title compound is prepared according to the procedure 3.01b,starting from building block 3.03a and a 40% solution of dimethylaminein water; LC-MS method D: t_(R)=0.82 min; [M+H]+=340.16.

3.02: rac-(3R*,4R*)-4-Amino-1-cyclopentyl-piperidine-3-carboxylic aciddimethylamide

The title compound is prepared according to the procedure 3.01, startingfrom building block 3.03b; LC-MS method D: t_(R)=0.59 min;[M+H]⁺=240.18.

BB 3.04:rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)-amide, dihydrochloride 3.04a:rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopropylmethyl-piperidine-3-carboxylicacid

The title compound is prepared according to the procedure 3.01a,starting from building block 1.04a; LC-MS method D: t_(R)=0.47 min;[M+H]⁺=299.13.

3.04b:rac-[(3R*,4R*)-1-Cyclopropylmethyl-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

The title compound is prepared according to the procedure 3.01b,starting from building block 3.04a and 1-(2-pyridyl)cyclopropylaminedihydrochloride; LC-MS method D: t_(R)=0.85 min; [M+H]⁺=415.17.

3.04 rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide, dihydrochloride

The title compound is prepared according to the procedure 3.01, startingfrom building block 3.04b; LC-MS method D: t_(R)=0.64 min;[M+H]⁺=315.18.

BB 3.05:rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide dihydrochloride 3.05b:rac-[(3R*,4R*)-1-Cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

The title compound is prepared according to the procedure 3.01b,starting from building block 3.04a and 1-(2-pyrimidyl)cyclopropylaminehydrochloride; LC-MS method A: t_(R)=0.64 min; [M+H]⁺=416.34.

3.05 rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide, dihydrochloride

The title compound is prepared according to the procedure 3.01, startingfrom building block 3.04b; LC-MS method A: t_(R)=0.38 min;[M+H]⁺=316.34.

General Procedures for the Preparation of Compounds 3.001 to 3.022Method I:

To a solution of the respective amine (BB 3.01 to BB 3.05) (0.08 mmol)in 0.7 mL DMF is added the respective carboxylic acid (commerciallyavailable or of Structure A-4) (0.08 mmol). DIPEA (0.336 mmol) is thenadded followed by HATU (0.084 mmol). The reaction mixture is stirred 21h at RT. Up to 0.28 mmol of a 2M HCl solution is added to the crudemixture to dissolve the precipitate, and the clear solution is directlypurified by prep. LC-MS with method E.

Method J:

A solution of the respective amine (BB 3.01 to BB 3.05) (0.3 mmol) intoluene (0.4 mL) at 0° C. under argon is treated with a 2M solution oftrimethylaluminium in toluene (0.3 mmol). After stirring for 30 min at0° C., a solution of an ester of Structure A-4 (L1=O-alkyl) (0.1 mmol)in toluene (0.4 mL) is added and the mixture stirred at RT for 4 to 22hours. The reaction mixture is quenched with a 1.25M solution of HCl inmethanol (0.6 mmol) and the solvents are evaporated. The crude residueis purified by prep. LC-MS using method E.

Example 3.001:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide

To a solution ofrac-(3R*,4R*)-4-amino-1-cyclohexyl-piperidine-3-carboxylic aciddimethylamide (20.3 mg, 0.08 mmol) in DMF (0.7 mL) is added5-(2,6-difluoro-phenyl)-isoxazole-3-carboxylic acid (18 mg, 0.08 mmol).DIPEA (0.044 mL, 0.256 mmol) is then added followed by HATU (31.9 mg,0.084 mmol). The reaction mixture is stirred 21 h at RT. Up to 0.28 mmolof a 2M HCl solution is added to the crude mixture to dissolve theprecipitate, and the clear solution is directly purified by prep. LC-MSwith method E. LC-MS method D: t_(R)=0.61 min; [M+H]⁺=461.

Compounds of Examples 3.002 to 3.022 listed in Table 3 below areprepared by applying one of the above-mentioned general procedures I orJ to the building blocks BB-3.01 BB-3.05 coupled with respectivecarboxylic acid or ester of Structure A-4 (L¹=OH or O-alkyl), which iscommercially available or prepared according to/in analogy to themethods described above.

Enantiomerically pure compounds are obtained using one of the abovementioned chiral preparative chromatography methods.

TABLE 3 Examples 3.001a-3.022 QC LC-MS Mass Example Found Nr SubstanceName t_(R) (min) [M + H]⁺ 3.001rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.61 461 amino}-piperidine-3-carboxylic acid dimethylamide 3.002rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.62 443 amino}-piperidine-3-carboxylic acid dimethylamide 3.003rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-0.54 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide3.003a(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-0.54 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide(enantiomer 1) 3.003b(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-0.54 462 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide(enantiomer 2) 3.004rac-(3R*,4R*)-4-{[5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.67 477.1 1-cyclohexyl-piperidine-3-carboxylic acid dimethylamide 3.005rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.63 479.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide3.006rac-(3R*,4R*)-4-{[5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-0.69 477 1-cyclohexyl-piperidine-3-carboxylic acid dimethylamide 3.007rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-0.56 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide3.009rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3-carbonyl]-0.62 532.2 amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)-amide 3.010rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-0.57 551 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 3.011rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-3-carbonyl]-0.61 550.3 amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)-amide 3.012rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-0.56 551.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 3.013rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3-0.56 504.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 3.014rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-fluoro-phenyl)-isoxazole-3-0.58 504.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 3.015rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-0.56 522.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 3.016rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.5 523.1[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin- 2-yl-cyclopropyl)-amide 3.016a(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-0.51 523.1 carbony]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide or(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin- 2-yl-cyclopropyl)-amide (1^(st) eluted enantiomer) 3.017rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-0.57 447.3 amino}-piperidine-3-carboxylic acid dimethylamide 3.018rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-0.61 461.3 amino}-piperidine-3-carboxylic acid dimethylamide 3.019rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-5-0.59 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide3.020a(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.61 541.28 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide (enantiomer 1) 3.020b(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-0.61 541.41 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide (enantiomer 2) 3.021rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-0.60 523.4 3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 3.022rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-0.60 541 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 3.022a(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-0.60 541.4 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide or(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide (1^(st) eluted enantiomer)

General Method D for the Synthesis of Piperidines of Formula (I)Buildings Blocks Preparation of Building Blocks of Structure 1

BB-4.01(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 4.01a:4-((S)-1-Phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

In a dry flask equipped with a Dean-Stark trap and reflux condenser,4-oxopiperidine-1,3-dicarboxylic acid-1-t-butyl ester 3-methyl ester (10g, 35 mmol) is dissolved in toluene (500 mL).(S)-(−)-α-methylbenzylamine (6.36 g, 52.5 mmol) and p-toluenesulfonicacid monohydrate (0.34 g, 1.75 mmol) are added and the mixture is heatedto reflux for 3 h. The mixture is then cooled to RT, washed three timeswith aq.sat. NaHCO₃ (3×100 mL) and dried over MgSO₄, filtered andconcentrated under reduced pressure to yield the product as a thickyellow oil. LC-MS method A: t_(R)=1.01 min; [M+H]⁺=375.18. ¹H NMR (400MHz, CDCl₃) δ: 9.28 (d, J=7.4 Hz, 1H), 7.25-7.38 (m, 5H), 4.63 (quint,J=6.7 Hz, 1H), 4.19 (q, J=7 Hz, 2H), 4.07 (s, 2H) 3.46-3.38 (m, 1H)3.33-3.26 (m, 1H), 2.43-35 (m, 1H), 2.09-1.99 (m, 1H), 1.50 (d, J=7.4Hz, 3H), 1.43 (s, 9H), 1.29 (t, J=7.0 Hz, 3H).

4.01b: (3S,4S)-4-((S)-1-Phenyl-ethylamino)-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

Sodium borohydride (5.19 g, 137 mmol) is added portionwise under N₂ to asolution of isobutyric acid (68.1 mL, 734 mmol) in toluene (22 mL) at 0°C. The mixture is further stirred at RT for 20 min. The mixture iscooled again to 0° C. A solution of4-((S)-1-Phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester(13 g, 34.7 mmol) in toluene (50mL) is slowly added and the resulting mixture is stirred for 60 min at0° C. Additional sodium borohydride (817 mg, 21.6 mmol) is added in fiveportions over a 4 h period. Water (100 mL) is added carefully and thereaction mixture is stirred for 15 min at RT. A 3M aq.NaOH solution isadded to bring the mixture to pH 10. The reaction mixture is extractedwith EtOAc (3×150 mL), the combined organic layers are dried with MgSO₄and the solvent is evaporated under reduced pressure. The resultingyellow oil is purified on a plug of silica gel and chromatographied withheptane/EtOAc 2:1 to give a yellowish oil. This oil is dissolved in dryethanol (50 mL) under N₂ and the resulting solution is transfered to asolution prepared in advance by mixing sodium ethoxyde in ethanol (20 mLof 21 w %, 52 mmol) and EtOAc (7.6 mL, 78 mmol). The resulting solutionis stirred at 50° C. under N₂ for 15 h. The solvent is removed underreduced pressure, brine (150 mL) is added and the pH of the resultingsolution is brought to pH=10 with 1 N aq. NaOH. The resulting mixture isextracted with EtOAc (3×100 mL). The combined organic layers are driedover Mg SO₄ and concentrated under reduced pressure. The resulting oilis purified by flash chromatography over 100 g of silica gel withHeptane/EtOAc system (10:0 to 1:1 gradient) as eluent. The combinedfractions are concentrated and dried under vacuum over night to obtain apale yellow oil. This oil is dissolved in diethyl ether (10 mL) and 4 NHCl in dioxane (1.45 mL, 5.8 mmol) is added dropwise. The solution isstirred for 30 min and a precipitate is formed during this time. Theprecipitation is completed by adding heptane (28.7 mL) and storing themixture at 0° C. for 1 h. The precipitate is isolated by filtration andwashed with heptane to yield 2.57 g of an off-white solid. The solid issuspended in acetonitrile (4.6 mL) and heated to reflux until the solidhas dissolved completely. The solution is then cooled to 0° C.overnight. The resulting crystals are isolated by filtration and washed3× with 1.15 mL portions of cold acetonitrile to yield the hydrochloridesalt as a colorless solid. The salt is then stirred in aq. 10% NaHCO₃solution (25 mL) and extracted with DCM (2×20 mL). Evaporation of theorganic layers under reduced pressure yields the title product as acolorless oil. LC-MS method A: t_(R)=0.73 min; [M+H]⁺=377.29 ¹H NMR (400MHz, CDCl₃) 5: 7.79-7.40 (m, 5H), 4.13-4.24 (m, 3H), 3.70-4.09 (m, 2H),2.82-2.99 (m, 2H), 2.58-2.72 (m, 1H), 2.21-2.38 (m, 1H), 1.62-1.76 (m,1H), 1.45 (m, 9H), 1.20-1.35 (m, 7H), 1.02-1.14 (m, 1H).

4.01c: (3S,4S)-4-Amino-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester

A solution of(3S,4S)-4-((S)-1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (1.833 g, 5.06 mmol) in MeOH (7 mL) isadded to a suspension of palladium on activated charcoal (10%) (183 mg,0.172 mmol) and ammonium formate (2.63 g, 40.5 mmol) in MeOH (40 mL)under N₂. The mixture is refluxed for 6 h. After the reaction iscomplete (disappearance of the peak but also exchange of the ethyl- forthe methyl ester) the cooled solution is filtered through Celite, andthe filtrate is concentrated to obtain the title product as a slightlyyellow oil. LC-MS method A: t_(R)=0.53 min; [M+H]⁺=259.23. ¹H NMR (400MHz, CDCl₃) δ: 3.87-3.49 (m, 4H), 3.70 (s, 3H), 3.31 (m, 1H), 2.43-1.75(m, 5H), 1.43 (s, 9H).

4.01d:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

To a solution of (3S,4S)-4-amino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (1 g, 3.87 mmol) in DMF (8 mL) at RTis added 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (1.3 g, 5.81mmol). DIPEA (2.12 mL, 12.4 mmol) is then added followed by HATU (1.55g, 4.06 mmol). The reaction mixture is stirred overnight at RT. Thereaction mixture is concentrated, dissolved in DCM (100 mL) and treatedtwice with aq. sat. NaHCO₃ (100 mL). The organic layer is dried overMgSO₄ and evaporated. The crude residue is purified by flashchromatography over 40 g of silica gel with heptane/EtOAc system (1:0 to3:1) as eluent to yield the title compound as white powder; LC-MS methodA: t_(R)=0.94 min; [M+H]⁺=466.04. ¹H NMR (400 MHz, CDCl₃) δ: 7.23-7.36(m, 1H), 7.96 (m, 1H), 6.96-7.12 (m, 3H), 6.79-6.91 (m, 1H), 4.29-4.51(m, 2H), 4.00-4.22 (m, 1H), 3.64-3.78 (m, 3H), 2.85-3.09 (m, 2H),2.50-2.68 (m, 1H), 2.10-2.27 (m, 1H), 1.42-1.69 (m, 11H), 1.21-1.38 (m,1H).

4.01e:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride

(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (1152 mg, 2.48 mmol) is dissolvedin DCM (15 mL). HCl in dioxane 4M (12.4 mL, 49.5 mmol) is addeddropwise. The mixture is stirred at RT for 1 hour. The solvents areevaporated and the residue is dried on HV to deliver the title crudecompound as a white powder. LC-MS method A: t_(R)=0.61 min;[M+H]⁺=366.18.

4.01f:(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

To a suspension of(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride (0.99 g, 2.48 mmol) in DCM (20 mL) at RTis added cyclohexanone (0.75 mL, 6.9 mmol) followed by acetic acid (0.44mL, 7.7 mmol) and sodium triacetoxyborohydride (1.58 g, 7.45 mmol). Thereaction mixture is stirred overnight at RT. The reaction mixture isdiluted with DCM (30 mL) and treated with aq. sat. NaHCO₃ twice (50 mL).The organic phase is dried over MgSO₄ and evaporated. The crude titlecompound is obtained; LC-MS method A: t_(R)=0.71 min; [M+H]⁺=448.17.

4.01:(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester (1214 mg, 2.71 mmol) is dissolved in THF (14 mL) and 1M aq.

LiOH solution (6.98 mL, 6.98 mmol) is added. The mixture is stirredovernight at RT. 1M aq. HCl solution (6.98 mL, 6.98 mmol) is added andthe reaction is stirred for 5 min. The solvents are evaporated to givethe title compound as a yellow solid. LC-MS method A: t_(R)=0.66 min;[M+H]⁺=434.06.

Preparation of Building Blocks of Structure 1 Used as Intermediates inthe Preparation of Examples 4.001 to 4.102

The following carboxylic acids are prepared in analogy to exampleBB-4.01:

BB-4.02:(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 4.02a:4-((R)-1-Phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

The title compound is prepared according to reaction 4.01a describedabove using 4-oxopiperidine-1,3-dicarboxylic acid-1-t-butyl ester3-ethyl ester and (R)-(−)-α-methylbenzylamine; LC-MS method A:t_(R)=1.01 min; [M+H]⁺=375.28.

4.02b: (3R,4R)-4-(R)-1-Phenyl-ethylamino)-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

The title compound is prepared according to reaction 4.01b describedabove by reduction of4-((R)-1-phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester with a mixture of sodiumborohydride and isobutyric acid followed by epimerisation with sodiumethoxide in EtOH and EtOAc; LC-MS method A: t_(R)=0.72 min;[M+H]⁺=377.27.

4.02c: (3R,4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester

The title compound is prepared according to reaction 4.01c describedabove by treatment of(3R,4R)-4-(R)-1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester with palladium on activated charcoal(10%)) and ammonium formate in MeOH; LC-MS method A: t_(R)=0.52 min;[M+H]⁺=259.22.

4.02d:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

The title compound is prepared according to reaction 4.01d by treatmentof (3R,4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester with 5-(2,4-difluorophenyl)isoxazole-3-carboxylic Acid;LC-MS A: t_(R)=0.94 min; [M+H]⁺=466.02.

4.02e:(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride

The title compound is prepared according to reaction 4.01e by treatmentof(3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester with HCl in Dioxane 4M; LC-MSmethod A: t_(R)=0.61 min; [M+H]⁺=366.14.

4.02f:(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to reaction 4.01f by treatmentof(3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride with cyclohexanone and sodiumtriacetoxyborohydride; LC-MS method A: t_(R)=0.72 min; [M+H]⁺=448.19.

4.02:(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01 by treatmentof(3R,4R)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester 1 M aq. LiOH solution. LC-MS method A: t_(R)=0.66 min;[M+H]⁺=434.07.

BB-4.03:(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 4.03f:(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to reaction 4.01f by treatmentof(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride with cyclopropanecarbaldehyde and sodiumtriacetoxyborohydride; LC-MS method D: t_(R)=1.02 min; [M+H]⁺=420.12.

4.03:(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01 by treatmentof(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester with 1 M aq. LiOH solution. LC-MS method D: t_(R)=0.54min; [M+H]⁺=405.79.

BB-4.04:(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 4.04f:(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to reaction 4.01f by treatmentof(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride with cyclopentanone and sodiumtriacetoxyborohydride; LC-MS method D: t_(R)=1.04 min; [M+H]⁺=434.14.

4.04g:(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01 by treatmentof(3S,4S)-1-cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester with 1 M aq. LiOH solution. LC-MS method D: t_(R)=0.56min; [M+H]⁺=420.09.

BB-4.05:(3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 4.05f:(3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl ester

The title compound is prepared by treatment of(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl ester hydrochloride with bromoacetonitrile and DIPEA in EtOH;LC-MS method A: t_(R)=0.95 min; [M+H]⁺=419.19.

4.05:(3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01 by treatmentof(3S,4S)-1-cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl ester with 1 M aq. LiOH solution. LC-MS method D: t_(R)=0.81min; [M+H]⁺=391.20.

BB-4.06:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylicacid

4.06c: (3R,4S)-4-Amino-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-ethyl ester

The title compound is prepared according to reaction 4.01c describedabove by treatment of(3R,4S)-4-(R)-1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester with palladium hydroxide on activatedcharcoal 20%)) and hydrogen in EtOH at 20 bar and 80° C.; LC-MS methodD: t_(R)=0.81 min; [M+H]⁺=273.21

4.06d:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

The title compound is prepared according to reaction 4.01d by treatmentof (3S,4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-ethyl ester with 5-(2,4-difluorophenyl)isoxazole-3-carboxylic Acidfollowed by epimerization with sodium ethoxyde in ethanol; LC-MS A:t_(R)=0.96 min; [M+H]⁺=480.17.

4.06e:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl ester hydrochloride

The title compound is prepared according to reaction 4.01e by treatmentof(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester with HCl in dioxane 4M; LC-MSmethod A: t_(R)=0.70 min; [M+H]⁺=380.18.

4.06f:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylicacid ethyl ester

The title compound is prepared by treatment of(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl ester hydrochloride with 1-fluorocyclopropane-1-carbaldehydeand sodium triacetoxyborohydride; LC-MS method A: t_(R)=0.78 min;[M+H]⁺=452.19.

4.06:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01 by treatmentof(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylicacid ethyl ester with 1 M aq. LiOH solution. LC-MS method D: t_(R)=0.69min; [M+H]⁺=424.20.

BB-4.07:(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 4.07f:(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to reaction 4.01f by treatmentof(3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride with cyclopropanecarbaldehyde and sodiumtriacetoxyborohydride; LC-MS method A: t_(R)=0.7 min; [M+H]⁺=420.14.

4.07:(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01 by treatmentof(3R,4R)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t_(R)=0.64min; [M+H]⁺=406.06.

BB-4.08(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

4.08f:(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to reaction 4.01f by treatmentof(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride with cyclobutanone and sodiumtriacetoxyborohydride; LC-MS method A: t_(R)=0.76 min; [M+H]⁺=420.21.

4.08:(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01g by treatmentof(3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t_(R)=0.64min; [m+H]⁺=406.33.

BB-4.09(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid 4.09f:(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to reaction 4.01f by treatmentof(3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride with cyclobutanone and sodiumtriacetoxyborohydride; LC-MS method A: t_(R)=0.77 min; [M+H]⁺=419.83.

4.09:(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01g by treatmentof(3R,4R)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t_(R)=0.69min; [M+H]⁺=406.22.

BB-4.10:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylicacid 4.10f:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylicacid methyl ester

The title compound is prepared according to reaction 4.01f by treatmentof(3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester hydrochloride with acetaldehyde and sodiumtriacetoxyborohydride; LC-MS method A: t_(R)=0.66 min; [M+H]⁺=394.35.

4.10:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01g by treatmentof(3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t_(R)=0.62min; [M+H]⁺=380.96.

BB-4.11:rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

4.11a: 4-Amino-1-tert-butyl-1,2,5,6-tetrahydro-pyridine-3-carboxylicacid methyl ester A solution of LiHMDS 1M in THF (6.73 mL, 6.73 mmol,1.1 eq) is added dropwise at −78° C. to a solution of1-tert-butylpiperidin-4-one (1000 mg, 6.12 mmol) in THF (10 mL) underargon. The mixture is stirred at this temperature for 1 h. Then methylcyanoformate (0.486 mL, 6.12 mmol) is added and the reaction is stirredat −78° C. for 1 h. MeOH (30 mL) is added at −78° C., followed byammonium acetate (4813 mg, 61.2 mmol). the mixture is stirred at thistemperature for a 15 minutes and then allowed to warm to RT and stirredfor 18 h. The solvents are evaporated under reduced pressure. Theresidue is taken up in DCM (25 mL) and washed with sat. aq. NaHCO₃ (25mL). The aq. phase is extracted twice with DCM (2×25 mL). The organicphase is washed with brine (25 mL). The combined organic layers aredried over MgSO₄, filtered and concentrated to deliver the crude titlecompound as a yellowish oil; LC-MS method A: t_(R)=0.43 min;[M+H]⁺=213.46.

4.11b: rac-[R*,R*]-Methyl-4-amino-1-(tert-butyl)piperidine-3-carboxylateand rac-[R*,S*]-methyl 4-amino-1-(tert-butyl)piperidine-3-carboxylate

A solution of4-amino-1-tert-butyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acidmethyl ester (1.29 g, 6.12 mmol) in methanol (10 mL) is treated withNaBH₃CN (774 mg, 12.3 mmol) and AcOH (1.06 mL, 9.25 mmol) at 0° C. Thenthe reaction is let to warm to RT. The reaction is stirred at 50° C. for1 h. NaBH₃CN (387 mg, 6.15 mmol, 1 eq) is added and the reaction isheated at 50° C. for 18 h. MeOH is evaporated under reduced pressure andthe residue is taken up in DCM (20 mL) and washed with sat. aq. NaHCO₃(20 mL). The aq. phases are extracted twice (2×15 mL) with DCM and theorganic phases are combined, dried over MgSO₄, filtered and concentratedunder reduced pressure to yield the crude title product as a yellowishoil; LC-MS method A: t_(R)=0.21 min; [M+H]⁺=215.34.

4.11c:rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester

A solution of rac-[R*,R*]-methyl4-amino-1-(tert-butyl)piperidine-3-carboxylate and rac-[R*,S*]-methyl4-amino-1-(tert-butyl)piperidine-3-carboxylate (659 mg, 3.08 mmol) inDCM (5 mL), is treated with 5-(2,4-difluorophenyl)isoxazole-3-carboxylicacid (714 mg, 3.08 mmol), HATU (2338 mg, 3.08 mmol), and DIPEA (0.526mL, 3.08 mmol). The reaction mixture is stirred at RT for 1 h30. DCM (10mL) and sat. aq. NaHCO₃ solution (10 mL) are added to the mixture. Theorganic phase is separated, the aq. phase is extracted with DCM (2×10mL), the combined organic phases are dried over MgSO₄, filtered andevaporated. The crude is purified by prep. LC-MS with method E to obtainthe title compound as a colorless oil; LC-MS method A: t_(R)=0.71 min;[M+H]⁺=422.33.

4.11:rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid

The title compound is prepared according to reaction 4.01g by treatmentofrac-(3R*,4R*)-1-tert-butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t_(R)=0.64min; [M+H]⁺=408.35.

Example 4.001:(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-methyl-cyclopropyl)-amide

To a solution of(3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (21.7 mg, 0.05 mmol) in DMF (0.55 mL) is added1-methylcyclopropan-1-amine hydrochloride (11.3 mg, 0.1 mmol). DIPEA(0.028 mL, 0.16 mmol) is then added followed by HATU (20 mg, 0.052mmol). The reaction mixture is stirred overnight at RT. The crudemixture is directly purified by prep. LC-MS with method E. LC-MS methodD: t_(R)=0.66 min; [M+H]⁺=487.2.

Compounds of Examples 4.001 to 4.102 listed in Table 4 below areprepared by applying one of the above-mentioned general procedures A, Bor C to the building blocks BB-4.01 BB-4.11 coupled with commerciallyavailable amines or amine BB-9.01 of general structure 2.Enantiomerically pure compounds are obtained using one of the abovementioned chiral preparative chromatography methods.

TABLE 4 Examples 4.002-4.102 QC LC-MS Mass Example Found Nr SubstanceName t_(R) (min) [M + H]⁺ 4.001(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.66 487.2 amino}-piperidine-3-carboxylic acid(1-methyl-cyclopropyl)-amide 4.002(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.71 519.2 amino}-piperidine-3-carboxylic acid(2-methoxy-1,1-dimethyl-ethyl)-amide 4.003(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.72 533.4 amino}-piperidine-3-carboxylic acid(3-methoxy-1,1-dimethyl-propyl)-amide 4.004(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.72 568.1 amino}-piperidine-3-carboxylic acid[1-(5-fluoro-pyridin-2-yl)-cyclopropyl]- amide 4.005(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 461 amino}-piperidine-3-carboxylic acid dimethylamide 4.006(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.73 501.3 amino}-piperidine-3-carboxylic acid(1-methyl-cyclobutyl)-amide 4.007(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 529.3 amino}-piperidine-3-carboxylic acid((1RS)-1-[1,2,4]oxadiazol-3-yl-ethyl)- amide (mixture of isomers) 4.008(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.71 556.3 amino}-piperidine-3-carboxylic acid[(1RS)-1-(5-fluoro-pyridin-2-yl)-ethyl]- amide (mixture of isomers)4.009(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.76 515.2 amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)-amide 4.010(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.77 537.4 amino}-piperidine-3-carboxylic acid((R)-1-phenyl-ethyl)-amide 4.011(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.67 553.4 amino}-piperidine-3-carboxylic acid((S)-2-hydroxy-1-phenyl-ethyl)-amide 4.012(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.72 523.4 amino}-piperidine-3-carboxylic acid benzylamide 4.013(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.58 554.2 amino}-piperidine-3-carboxylic acid((1RS)-2-hydroxy-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 4.014(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.77 515.2 amino}-piperidine-3-carboxylic acid((R)-1-cyclobutyl-ethyl)-amide 4.015(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.73 489 amino}-piperidine-3-carboxylic acid tert-butylamide 4.016(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.73 501.3 amino}-piperidine-3-carboxylic acid(1-methyl-cyclobutyl)-amide 4.017(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.56 433.3 amino}-piperidine-3-carboxylic acid amide 4.018(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.66 487 amino}-piperidine-3-carboxylic acid(1-methyl-cyclopropyl)-amide 4.019(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.65 500.3 amino}-piperidine-3-carboxylic acid(cyano-dimethyl-methyl)-amide 4.020(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.67 553.4 amino}-piperidine-3-carboxylic acid((S)-2-hydroxy-1-phenyl-ethyl)-amide 4.021(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.68 553.3 amino}-piperidine-3-carboxylic add((R)-2-hydroxy-1-phenyl-ethyl)-amide 4.022(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.75 537.4 amino}-piperidine-3-carboxylic add ((R)-1-phenyl-ethyl)-amide4.023(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.55 499.1 carbonyl]-amino}-piperidine-3-carboxylic acid[(1RS)-1-(2H-pyrazol-3-yl)- ethyl]-amide (mixture of isomers) 4.024(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.49 510.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyridin-3-yl-ethyl)- amide 4.025(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.61 523.3 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 4.026(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.43 536.1 amino}-piperidine-3-carboxylic acid(1-pyridin-4-yl-cyclopropyl)-amide 4.027(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.41 522.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-4-yl-cyclopropyl)- amide 4.028(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.61 536.1 amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)-amide 4.029(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.62 537.3 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 4.030(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 538.2 amino}-piperidine-3-carboxylic acid(1-methyl-1-pyridin-2-yl-ethyl)-amide 4.031(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.59 522.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropyl)- amide 4.032(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.61 523.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 4.033(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.61 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-methyl-1-pyridin-2-yl- ethyl)-amide 4.034(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.64 541.1 amino}-piperidine-3-carboxylic acid[1-methyl-1-(1-methyl-1H-pyrazol-4-yl)- ethyl]-amide 4.035(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.65 543.1 amino}-piperidine-3-carboxylic acid[1-methyl-1-(5-methyl-[1,2,4]oxadiazol- 3-yl)-ethyl]-amide 4.036(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.69 499.3 amino}-piperidine-3-carboxylic acid bicyclopropyl-1-ylamide4.037(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.65 517.4 amino}-piperidine-3-carboxylic acid[(1RS)-1-(tetrahydro-furan-2-yl)-ethyl]- amide (mixture of isomers)4.038(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.55 514 amino}-piperidine-3-carboxylic acid[(1RS)-1-(1H-[1,2,4]triazol-3-yl)-ethyl]- amide (mixture of isomers)4.039(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 471.3 amino}-piperidine-3-carboxylic acid((1RS)-1-methyl-prop-2-ynyl)-amide (mixture of isomers) 4.04(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.63 514.3 amino}-piperidine-3-carboxylic acid((1RS)-1-isoxazol-3-yl-ethyl)-amide (mixture of isomers) 4.041(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.56 513.1 amino}-piperidine-3-carboxylic acid[(1RS)-1-(2H-pyrazol-3-yl)-ethyl]-amide (mixture of isomers) 4.042(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.5 524.1 amino}-piperidine-3-carboxylic acid((R)-1-pyridin-3-yl-ethyl)-amide 4.043(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.63 527.2 carbonyl]-amino}-piperidine-3-carboxylic acid[1-methyl-1-(1-methyl-1H- pyrazol-4-yl)-ethyl]-amide 4.044(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.64 529.1 carbonyl]-amino}-piperidine-3-carboxylic acid[1-methyl-1-(5-methyl- [1,2,4]oxadiazol-3-yl)-ethyl]-amide 4.045(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.67 485.3 carbonyl]-amino}-piperidine-3-carboxylic acidbicyclopropyl-1-ylamide 4.046(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.64 503.3 carbonyl]-amino}-piperidine-3-carboxylic acid[(1RS)-1-(tetrahydro-furan-2- yl)-ethyl]-amide (mixture of isomers)4.047(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.53 500.1 carbonyl]-amino}-piperidine-3-carboxylic acid[(1RS)-1-(1H-[1,2,4]triazol-3- yl)-ethyl]-amide (mixture of isomers)4.048(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.62 457.3 carbonyl]-amino}-piperidine-3-carboxylic acid((1RS)-1-methyl-prop-2-ynyl)- amide (mixture of isomers) 4.049(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.61 500.3 carbonyl]-amino}-piperidine-3-carboxylic acid((1RS)-1-isoxazol-3-yl-ethyl)- amide (mixture of isomers) 4.050(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6538.4 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(1-oxy-pyridin-2-yl)- cyclopropyl]-amide 4.051(3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.9 508.3 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 4.052(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-0.6 541 fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid(1-pyrimidin-2-yl- cyclopropyl)-amide 4.053(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7521.4 carbonyl]-amino}-piperidine-3-carboxylic acid(1-phenyl-cyclopropyl)-amide 4.054(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7540.2 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(3-fluoro-pyridin-2-yl)- cyclopropyl]-amide 4.055(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6523.2 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-4-yl-cyclopropyl)- amide 4.0561-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.7 517.4carbonyl]-amino}-piperidine-3-carbonyl)-amino]-cyclopropanecarboxylicacid ethyl ester 4.057(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8535.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-phenyl-cyclobutyl)-amide 4.058(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8541.4 carbonyl]-amino}-piperidine-3-carboxylic acidbenzyl-(2-fluoro-ethyl)-amide 4.059(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7551.1 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(3-methoxy-phenyl)- cyclopropyl]-amide 4.060(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8589.4 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(2-trifluoromethyl-phenyl)- cyclopropyl]-amide 4.061(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7539.1 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(2-fluoro-phenyl)- cyclopropyl]-amide 4.062(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.0539 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(4-fluoro-phenyl)-cyclopropyl]-amide 4.063(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7539 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(3-fluoro-phenyl)-cyclopropyl]-amide 4.064(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5510 carbonyl]-amino}-piperidine-3-carboxylic acid(6-methyl-pyridin-2-ylmethyl)- amide 4.065(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.86 543.2 carbonyl]-amino}-piperidine-3-carboxylic acid[2-(2-chloro-phenyl)-ethyl]- amide 4.066(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7461 carbonyl]-amino}-piperidine-3-carboxylic acid diethylamide 4.067a5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.7521.1cyclopropylmethyl-3-((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide or 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide (1^(st) eluted epimer) 4.067b5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.7521.1cyclopropylmethyl-3-((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide or 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1-cyclopropylmethyl-3-((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide (2^(nd) eluted epimer) 4.068(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8555 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(3-chloro-phenyl)-cyclopropyl]-amide 4.069(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6449.2 carbonyl]-amino}-piperidine-3-carboxylic acid methoxy-methyl-amide4.070(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7556.1 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(4-methyl-thiazol-2-yl)- cyclobutyl]-amide 4.071(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7461.1 carbonyl]-amino}-piperidine-3-carboxylic acid diethylamide 4.072(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7539.4 carbonyl]-amino}-piperidine-3-carboxylic acid[(R,S)-1-(2-methoxy-phenyl)- ethyl]-amide 4.072a(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8539.4 carbonyl]-amino}-piperidine-3-carboxylic acid[(R)-1-(2-methoxy-phenyl)- ethyl]-amide or(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid [(S)-1-(2-methoxy-phenyl)-ethyl]-amide (1^(st) eluted epimer) 4.073(R,S)-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-0.8 567.2 carbonyl]-amino}-piperidine-3-carbonyl)-amino]-phenyl-aceticacid ethyl ester 4.074(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8551 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(2-methoxy-phenyl)-cyclopropyl]-amide 4.075(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8587.1 carbonyl]-amino}-piperidine-3-carboxylic acid[(R)-1-(3-bromo-phenyl)- ethyl]-amide 4.076(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7537 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(2-hydroxy-phenyl)-cyclopropyl]-amide 4.077(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 1.0539.4 carbonyl]-amino}-piperidine-3-carboxylic acid[1-(1-oxy-pyrimidin-2-yl)- cyclopropyl]-amide 4.0785-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6 537cyclopropylmethyl-3-((R,S)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide 4.078b5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6537.4cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide or 5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide (2^(nd) eluted epimer) 4.079a5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6523.4cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide or 5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide (1st eluted epimer) 4.079b5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6 523cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide or 5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide (2nd eluted epimer) 4.080(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6511.1 carbonyl]-amino}-piperidine-3-carboxylic acid((R,S)-1-pyrimidin-2-yl-ethyl)- amide 4.080a(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6511 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrimidin-2-yl-ethyl)- amide or(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid((S)-1-pyrimidin-2-yl-ethyl)- amide (1st eluted epimer) 4.080b(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6511.4 carbonyl]-amino}-piperidine-3-carboxylic acid((R)-1-pyrimidin-2-yl-ethyl)- amide or(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid((S)-1-pyrimidin-2-yl-ethyl)- amide (2nd eluted epimer) 4.081(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6523.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-5-yl-cyclopropyl)- amide 4.082(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 540.4 amino}-piperidine-3-carboxylic acid[1-(3-fluoro-pyridin-2-yl)-cyclopropyl]- amide 4.083(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 525.1 amino}-piperidine-3-carboxylic acid(1-methyl-1-pyrimidin-2-yl-ethyl)-amide 4.084(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 511 amino}-piperidine-3-carboxylic acid((R,S)-1-pyrimidin-2-yl-ethyl)-amide 4.084b(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 511 amino}-piperidine-3-carboxylic acid((R)-1-pyrimidin-2-yl-ethyl)-amide or(3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((S)-1-pyrimidin-2-yl-ethyl)-amide(2nd eluted epimer) 4.085(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.7 551.1 amino}-piperidine-3-carboxylic acid(3-benzyl-oxetan-3-yl)-amide 4.086(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 552 amino}-piperidine-3-carboxylic acid[2-methyl-2-(3-methyl-pyridin-2-yl)- propyl]-amide 4.087(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 538.1 amino}-piperidine-3-carboxylic acid(2-methyl-2-pyridin-2-yl-propyl)-amide 4.088(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.8 535 amino}-piperidine-3-carboxylic acid(1-o-tolyl-cyclopropyl)-amide 4.089(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.7 555.1 amino}-piperidine-3-carboxylic acid[3-(4-fluoro-phenyl)-oxetan-3-yl]-amide 4.090(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.7 551 amino}-piperidine-3-carboxylic acid(3-phenyl-oxetan-3-ylmethyl)-amide 4.091(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.8 571.3 amino}-piperidine-3-carboxylic acid[2-(2-chloro-phenyl)-2-methyl-propyl]- amide 4.092(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.8 569.4 amino}-piperidine-3-carboxylic acid[1-(4-chloro-phenyl)-cyclopropylmethyl]- amide 4.093(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 536 amino}-piperidine-3-carboxylic acid(1-pyridin-2-yl-cyclopropylmethyl)- amide 4.094(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.7 571.1 amino}-piperidine-3-carboxylic acid[3-(3-chloro-phenyl)-oxetan-3-yl]-amide 4.095(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-0.5 498 piperidine-3-carboxylic acid[(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide 4.096(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-0.6 499 piperidine-3-carboxylic acid(1-methyl-1-pyrimidin-2-yl-ethyl)-amide 4.097(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.7 571.4 amino}-piperidine-3-carboxylic acid[3-(3-chloro-phenyl)-oxetan-3-yl]-amide 4.098(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 528 amino}-piperidine-3-carboxylic acid[(R,S)-1-(3-fluoro-pyridin-2-yl)-ethyl]- amide 4.098a(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 528 amino}-piperidine-3-carboxylic acid[(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]- amide or(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid[(S)-1-(3-fluoro-pyridin-2-yl)- ethyl]-amide (2nd eluted epimer) 4.099(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5497.2 carbonyl]-amino}-piperidine-3-carboxylic acid(pyrimidin-2-ylmethyl)-amide 4.100(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5497 carbonyl]-amino}-piperidine-3-carboxylic acid(pyrimidin-2-ylmethyl)-amide 4.101rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 525.4 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 4.101a(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 525 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1) 4.101b(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-0.6 525 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 2) 4.102(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6525 carbonyl]-amino}-piperidine-3-carboxylic acid(1-methyl-1-pyrimidin-2-yl- ethyl)-amide

General Method G for the Synthesis of Piperidines of Formula (I)Buildings Blocks Preparation of Building Blocks of Structure G-9

BB-5.01:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid dimethylamide 5.01a: 3-Methyl-4-oxo-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

A mixture of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester (1 g, 4 mmol), potassium carbonate (1.1 g, 8 mmol) andiodomethane (1.13 g, 8 mmol) in acetone (12 mL) is heated under refluxfor 7 h. The mixture is then cooled to RT and filtered through a frittedfilter. The filtrate is concentrated under reduced pressure to yield thetitle compound as a yellowish oil. LC-MS method A: t_(R)=0.78 min;[M+H]⁺=272.21.

5.01b: 4-Benzylamino-3-methyl-3,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

A solution of 3-methyl-4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (1.02 g, 3.78 mmol) in toluene (30 mL)is treated with benzylamine (0.51 g, 4.76 mmol) and p-toluenesulfonicacide monohydrate (36 mg). The resulting mixture is heated under refluxfor 2 h with a dean-stark condenser. The reaction mixture is extractedthree times with aq. sat. NaHCO₃. The organic phase is collected, driedover MgSO₄, filtered and the solvents evaporated to yield the crudeproduct as a yellow oil.

5.01c: rac-(3R*,4R*)-4-Benzylamino-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

The crude benzylamino-3-methyl-3,6-dihydro-2H-pyridine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (1.23g, 3.3 mmol) is dissolved inMeCN (15 mL) and cooled to 0° C. AcOH (0.38 mL, 6.6 mmol) is added.Sodium triacetoxyborohydride (3.84 g, 18.1 mmol) is added portionwise.The resulting mixture is stirred at 0° C. for 30 min and at RT for 2 h.The reaction mixture is concentrated under reduced pressure. The residueis dissolved in DCM (50 mL) and sat. aq. sodium carbonate solution (50mL) is added slowly. The organic layer is separated, the aq. phaseextracted again with DCM (50 mL) and the combined organic layers arewashed with brine (50 mL), dried over Na₂SO₄, filtered and evaporated.The two diastereomers are separated using silica gel columnchromatography. Evaporation of the lower fraction delivers the transisomer, as shown by 2D- and NOE NMR study, as a colorless oil. LC-MSmethod A: t_(R)=0.67 min; [M+H]⁺=363.22.

5.01d: rac-(3R*,4R*)-4-Amino-3-methyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

Dry Pd on activated charcoal 10% (27 mg, 0.0254 mmol) is added to asolution ofrac-(3R*,4R*)-4-benzylamino-3-methyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (0.3 g, 0.84 mmol) in MeOH (12 mL).After degassing the reaction flask, the mixture is hydrogenated for 1 hat ambient temperature. The reaction mixture is filtered to remove thecatalyst, and then concentrated to give the crude product as a yellowoil. LC-MS method A: t_(R)=0.53 min; [M+H]⁺=273.22.

5.01e:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

To a solution ofrac-(3R*,4R*)-4-amino-3-methyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (225 mg, 0.83 mmol) in DMF (5 mL) atRT is added 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (205 mg,0.91 mmol). DIPEA (0.283 mL, 1.65 mmol) is then added followed by HATU(346 mg, 0.91 mmol). The reaction mixture is stirred overnight at RT.The crude mixture is purified by prep. LC-MS in basic conditions. Thetitle compound is obtained as a pale yellow solid. LC-MS method A:t_(R)=1.01 Min; [M+H]⁺=480.14.

5.01f:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (240 mg, 0.5 mmol) is dissolvedin THF (4 mL) at RT. Aq. 1M LiOH solution (4 mL, 4 mmol) is then addedand the mixture stirred at RT for 72 h. The reaction mixture isacidified with 1M HCl solution (5 mL). The resulting suspension isextracted twice with DCM (10 mL). The organic layer is dried over MgSO₄and evaporated. The title compound is obtained as an off-white solid;LC-MS method A: t_(R)=0.91 min; [M+H]⁺=465.91.

5.018:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-3-methyl-piperidine-1-carboxylicacid tert-butyl ester

A solution ofrac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester (200 mg, 0.43 mmol) in DMF (6 mL) is treatedwith dimethylamine 2M solution in THF (0.277 mL, 0.554 mmol) and DIPEA(0.158 mL, 0.924 mmol). Then, HATU (193 mg, 0.508 mmol) is added and thereaction is stirred overnight. DMF is evaporated and the crude is takenup in DCM (10 mL) and extracted three times with NaHCO₃ sat sol. (10mL). The combined organic layers are washed with brine (20 mL), driedover sodium sulfate, filtered and evaporated to yield the product as aslightly orange oil, used as crude for the next step. LC-MS method A:t_(R)=0.97 min; [M+H]⁺=493.11.

5.01 h:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid dimethylamide

rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-3-methyl-piperidine-1-carboxylicacid tert-butyl ester (135 mg, 0.27 mmol) is dissolved in MeOH (5 mL) atRT. A 4M solution of HCl in dioxane (0.068 mL, 0.274 mmol) is added andthe reaction stirred at RT for 1 h. The reaction mixture isconcentrated, dissolved in DCM (10 mL) and treated with aq. sat. NaHCO₃(10 mL). The organic layer is separated and the aq. phase is extractedtwice with DCM (2×10 mL). The combined organic layers are dried overMgSO₄ and evaporated. The crude title compound is obtained; LC-MS A:t_(R)=0.64 min; [M+H]⁺=393.15.

Preparation of Building Blocks of Substituted Piperidines of Structure 1Used as Intermediates in the Preparation of Examples 5.002

In analogy to example BB-5.01 the following amide is prepared: BB-5.02(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide

5.02a:(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-34(R)-1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the reaction 5.01g describedabove usingrac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester and ((R)-1-pyridin-2-yl-ethyl)-amine; LC-MSmethod A: t_(R)=0.78 min; [M+H]⁺=570.12.

5.02:(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide

The title compound is prepared according to the reaction 5.01 hdescribed above by treating(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-3-((R)-1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester with 4M HCl in dioxane; LC-MS method A: t_(R)=0.56min; [M+H]⁺=470.09.

Example 5.001:(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide

A solution ofrac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide, cyclohexanone (0.046 mL, 0.45mmol) and AcOH (0.032 mL, 0.56 mmol) in DCM (5 mL) at RT is treated bysodium triacetoxyborohydride (149 mg, 0.67 mmol). The reaction mixtureis stirred overnight at RT. The reaction mixture is diluted with DCM (5mL) and washed with aq. sat. NaHCO₃ (10 mL). The organic layer is driedover MgSO₄ and evaporated. The crude residue is purified by prep. LC-MSin basic conditions. The title compound is obtained as a colorlesspowder. LC-MS method A: t_(R)=0.69 Min; [M+H]⁺=552.15.

Example 5.002:rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid dimethylamide

The title compound is prepared according to Example 5.001 describedabove by treatingrac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylicacid dimethylamide with cyclohexanone; LC-MS method A: t_(R)=0.76 min;[M+H]+=475.13.

Buildings Blocks Preparation of Building Blocks of Structure B-3

BB-6.01:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester 6.01a:4-Amino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-ten-butyl ester3-methyl ester

A solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester (10 g, 36.9 mmol), in MeOH (140 mL) is treated with 7Nammonia solution in MeOH (25 mL, 1.14 mol) and the resulting solution isheated under reflux for 18 h. The mixture is then cooled to RT andconcentrated under reduced pressure. The residue is taken up in DCM (100mL) and washed twice with water (2×100 mL) and brine (2×100 mL). Theorganic layer is dried over MgSO₄, filtered and concentrated underreduced pressure to yield the crude product as a yellow solid. LC-MSmethod A: t_(R)=0.83 min; [M+H-t-Bu]⁺=202.27.

6.01b: Mixture of rac-(3R*,4R*)-4-amino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester andrac-(3S*,4R*)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester

NaBH₄ (1.73 g, 45.7 mmol) is dissolved in THF (100 mL) and the resultingsolution is cooled to −18° C. TFA (13 mL, 169 mmol) is added over 20min. at −14° C. to −18° C. A solution of the crude4-amino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester (9.53 g, 33.9 mmol) in THF (15 mL) is added dropwise over10 min. The reaction is allowed to warm to 0° C. over 15 min and stirredat this temperature for 1 h. Water (50 mL) is poured onto the reactionmixture and stirring is continued for 10 min. The pH of the resultingsolution is brought to pH=11 with 10 N aq. NaOH. The mixture isextracted with DCM (2×100 mL). The combined organic layers are washedwith brine (2×100 mL), dried over Na₂SO₄, filtered and evaporated. Theproduct is obtained as a cis-trans mixture of products, as a yellowfoam: LC-MS method A: t_(R)=0.55 min; [M+H]⁺=259.34 and 0.58 min;[M+H]⁺=259.5.

6.01c: Mixture ofrac-(3S*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester andrac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

To a solution ofrac-(3R*,4R*)-4-amino-3-methyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester andrac-(3S*,4R*)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (7.1 g, 23.6 mmol) in DCM (75 mL) at RT is added5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (6.673 g, 29.1 mmol).DIPEA (9.98 mL, 58.3 mmol) is then added followed by T₃P 50% solution inDCM (34.7 mL, 58.3 mmol). The reaction mixture is stirred for 1 h30 atRT. The pH of the resulting solution is brought to pH=11 with 1 N aq.NaOH and the mixture is washed twice with aq. 1 N NaOH solution (2×100mL). The organic phase is dried over MgSO₄, filtered and concentratedunder reduced pressure to deliver a mixture of cis-trans products (4:1mixture) as a beige solid. LC-MS method A: t_(R)=1.07 Min; [M+H]⁺=465.94and t_(R)=1.10 Min; [M+H]⁺=465.94. The pure cis isomerrac-(3S*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester is obtained by suspending thecis-trans mixture in MeOH and then filtered off. LC-MS method A:t_(R)=1.07 Min; [M+H]⁺=465.96.

6.01d:rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester

Sodium methoxide solution 25 wt. % in MeOH (7.43 mL, 0.0325 mol) isadded to MeOH (15 mL) and methyl acetate (3.9 mL, 0.0488 mol). Themixture is refluxed for 30 min and cooled to RT. Then the mixture ofrac-(3S*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester andrac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester (8.37 g, 16.3 mmol) is suspendedunder nitrogen in dry MeOH (10 mL), and the resulting suspension isinjected into the NaOMe solution prepared previously. The mixture isstirred at RT for 1 day. The reaction mixture is treated with aq. sat.NaHCO₃ (10 mL) and MeOH is evaporated at reduced pressure. DCM (25 mL)is added to the residue. The organic phase is separated and the aq.layer is extracted 3× with DCM (3×25 mL). The combined organic layersare dried over MgSO₄, filtered and concentrated. The crude residue istriturated with MeCN (10 mL) to afford the title compound as an offwhite solid. LC-MS method A: t_(R)=1.07 Min; [M+H]⁺=465.94.

General Method I for the Synthesis of Piperidines of Formula (I)Buildings Blocks Preparation of Building Blocks of Structure 1-7

BB 7.01: (3S,4S)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

7.01a: (3R,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester

N-(Benzyloxycarbonyloxy)succinimide (12.2 g, 48.1 mmol) is added to asolution of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (13.1 g, 48.1 mmol) in THF (100 mL) at0° C. The reaction mixture is stirred for 10 min at 0° C. and then at RTfor 2 h. THF is evaporated and the residue is taken up in DCM (100 mL).The mixture is washed with aq.sat.NaHCO₃ (100 mL), dried over MgSO₄,filtered, concentrated and dried at HV to deliver the crude product as ayellowish oil. LC-MS method A t_(R)=1.01 min; [M+H]⁺=407.15.

7.01b: (3S,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester

Sodium ethoxide solution 21 wt. % in EtOH (77.4 mL, 0.0465 mol) is addedto EtOH (100 mL) and ethyl acetate (14.1 mL, 0.139 mol). The mixture isrefluxed for 30 min and cooled to RT. A suspension of(3R,4S)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester in dry ethanol (20 mL) is addeddropwise to the NaOEt solution at RT under nitrogen. The mixture isstirred at RT for 24 h. The reaction mixture is treated with water (10mL) and EtOH is evaporated at reduced pressure. Water (100 mL) is addedand the pH of the solution is adjusted to 5 by treatment with aq. 2NHCl. added to the residue. The aq. phase is extracted 3× with DCM (3×100mL). The combined organic layers are dried over MgSO₄ and filtered.Evaporation of the solvent gives the crude title compound as a yellowishoil, contaminated by 15% of the acid 7.01c. LC-MS method A: t_(R)=1.01Min; [M+H]⁺=407.13.

7.01c: (3S,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester

(3S,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester 7.01b (4.07 g, 10 mmol) is dissolved inTHF (50 mL) at RT. Aq. 1M NaOH solution (20 mL, 20 mmol) is added andthe mixture is stirred at RT for 18 h. The reaction mixture is acidifiedto around pH=3 with a 2M HCl solution (11 mL, 21 mmol) and evaporated.The resulting suspension is extracted twice with DCM (2×50 mL). Theorganic phase is dried over MgSO₄ and the solvent is evaporated to givethe title compound; LC-MS method A t_(R)=0.86 min; [M+H]⁺=379.18.

7.01d:(3S,4S)-4-Benzyloxycarbonylamino-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

A solution of(3S,4S)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester (4.26 g, 11.3 mmol) in DMF (40 mL) is treated with1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride (2.17 g, 12.4 mmol),DIPEA (10.2 mL, 58.5 mmol) and HATU (5.136 g, 13.5 mmol). The mixture isstirred 2 h at RT. Aq. saturated NaHCO₃ solution (50 mL) and DCM (80 mL)are added and the aq. phase is extracted with DCM (2×70 mL), dried overMgSO₄, filtered and evaporated. The crude is purified by Prep HPLC usingbasic conditions. The title compound is obtained as a yellowish foam.LC-MS method A: t_(R)=0.89 Min; [M+H]+=496.11.

7.01e:[(3S,4S)-3-(1-Pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid benzyl ester

(3S,4S)-4-Benzyloxycarbonylamino-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester (2622 mg, 5.29 mmol) in MeOH (35 mL) is treatedwith HCl 4M in dioxane (10.6 mL, 42.3 mmol). The reaction mixture isstirred at 50° C. for 2 h. After evaporation of the solvents, the crudeis dried under HV to give the crude title compound; LC-MS method Dt_(R)=0.56 min; [M+H]⁺=396.07.

7.01f:[(3S,4S)-1-Cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid benzyl ester

To a solution of[(3S,4S)-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid benzyl ester (3.06 g, 7.09 mmol) in DCM (100 mL) at RT is addedcyclopropanecarboxaldehyde (0.54 mL, 7.09 mmol) followed by DIPEA (3.64mL, 21.3 mmol) and sodium triacetoxyborohydride (3.96 g, 17.7 mmol). Thereaction mixture is stirred overnight. The reaction mixture is treatedwith aq. sat. NaHCO₃ (100 mL) and the resulting suspension is extractedtwice with DCM (2×100 mL). The organic phase is dried over MgSO₄ andevaporated. The crude is purified by Prep HPLC using basic conditions.The title compound is obtained as a light yellowish solid. LC-MS methodA: t_(R)=0.63 Min; [M+H]⁺=450.17.

7.01: (3S,4S)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide

A flask is purged with nitrogen, then charged with Pd/C 10% (50% wet)(160 mg, 1.5 mmol) and dry MeOH (10 mL) is added. A nitrogen purgedsuspension of[(3S,4S)-1-cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid benzyl ester (1349 mg, 3 mmol) in dry MeOH (20 mL) is added to thePd suspension. The atmosphere is exchanged with hydrogen and the mixtureis stirred at RT for 3 h. The mixture is filtered and evaporated. Thecrude is purified by Prep HPLC using basic conditions. The titlecompound is obtained as a light yellowish solid. LC-MS method A:t_(R)=0.34 Min; [M+H]+=316.34.

BB 7.02:rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 7.02a:rac-(3R*,4S1-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

The title compound is prepared according to the procedure 7.01a startingfrom building block rac-(3S*,4R*)-4-amino-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-methyl ester. LC-MS method A t_(R)=1.00 min;[M+H]⁺=393.26.

7.02b:rac-(3R*,4R*)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester

The title compound is prepared according to the procedure 7.01b startingfrom building block 7.0a. LC-MS method A: t_(R)=0.96 Min; [M+H]⁺=393.23.

7.02c:rac-(3R*,4R*)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester

The title compound is prepared according to the procedure 7.01c startingfrom building block 7.02b; LC-MS method A t_(R)=0.86 min; [M+H]⁺=379.25.

7.02d:rac-(3R*,4R*)-4-Benzyloxycarbonylamino-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 7.01d startingfrom building block 7.02c; LC-MS method A: t_(R)=0.88 Min;[M+H]⁺=496.25.

7.02e:rac-[(3R*,4R*)-3-(1-Pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid benzyl ester

The title compound is prepared according to the procedure 7.01e startingfrom building block 7.02d. LC-MS method D t_(R)=0.56 min; [M+H]⁺=396.27.

7.02f:rac-[(3R*,4*)-1-Cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamicacid benzyl ester

The title compound is prepared according to the procedure 7.01f startingfrom building block 7.02e. LC-MS method A: t_(R)=0.66 Min;[M+H]⁺=450.09.

7.02: rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

The title compound is prepared according to the procedure 7.01 startingfrom building block 7.02f. LC-MS method A: t_(R)=0.37 Min;[M+H]⁺=316.29.

Example 7.001:(3S,4S)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

To a solution of(3S,4S)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide (50 mg, 0.16 mmol) in DMF (5 mL) isadded 4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid (35.7 mg,0.08 mmol). DIPEA (0.067 mL, 0.396 mmol) is then added followed by HATU(72.3 mg, 0.19 mmol). The reaction mixture is stirred 21 h at RT. Up to0.28 mmol of a 2M HCl solution is added to the crude mixture to dissolvethe precipitate, and the clear solution is directly purified by prep.LC-MS with method E. LC-MS QC method: t_(R)=0.60 min; [M+H]⁺=523.1.

Compounds of Examples 7.002 to 7.016 listed in Table 5 below areprepared by applying one of the above-mentioned general procedures I orJ to the building blocks BB-7.01 BB-7.02 coupled with respectivecarboxylic acid or ester of Structure A-4 (L¹=OH or O-alkyl), which iscommercially available or prepared according to/in analogy to themethods described above.

Enantiomerically pure compounds are obtained using one of the abovementioned chiral preparative chromatography methods.

TABLE 5 Examples 7.002-7.016 LC-MS Mass Example Found Nr Substance Namet_(R) (min) [M + H]⁺ 7.002(3S,4S)-1-Cyclopropylmethyl-4-[(5-o-tolyl-isoxazole-3-carbonyl)-amino]-0.60 501.4 piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 7.003(3S,4S)-1-Cyclopropylmethyl-4-{[5-(3,4-dimethyl-phenyl)-isoxazole-3-0.70 515.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.004(3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-1.0 523.2 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.005(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dimethyl-phenyl)-isoxazole-3-0.70 515.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.006(3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-0.60 523.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.007(3S,4S)-1-Cyclopropylmethyl-4-{[5-(4-fluoro-phenyl)-oxazole-2-carbonyl]-0.6 505 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 7.008(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-0.5 524 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.009(3S,4S)-4-{[5-(4-Cyano-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.5 512cyclopropylmethyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.010(3S,4S)-1-Cyclopropylmethyl-4-{[4-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-0.6 523.4 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 7.011(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-0.6 523 amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide 7.012(3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4,6-trifluoro-phenyl)-1H-[1,2,3]triazole-1.0 541.4 4-carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.013(3S,4S)-1-Cyclopropylmethyl-4-{[5-(3,4-difluoro-phenyl)-isoxazole-3- 0.6523 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.014(3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isothiazole-5-0.6 539 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.015(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isothiazole-3-0.6 539.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide 7.016(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-0.6 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)- amide

General Method I for the Synthesis of Piperidines of Formula (I)Buildings Blocks Preparation of Building Blocks of Structure D-9

BB 8.01:(3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide 8.01a:(3R,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

To a solution of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester (1400 mg, 5.14 mmol)) in DMF (50 mL) atRT is added 1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid(1157 mg, 5.14 mmol). DIPEA (4.67 mL, 26.7 mmol) is then added followedby HATU (2346 mg, 6.17 mmol). The reaction mixture is stirred overnightat RT. The crude mixture is purified by prep. LC-MS in basic conditions.The title compound is obtained as a pale yellow solid. LC-MS method A:t_(R)=1.01 Min; [M+H]⁺=480.11.

8.01b:(3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

To a solution of(3R,4S)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (1587 mg, 3.41 mmol) in EtOH (14.9mL, 256 mmol) and EtOAc (7.36 mL, 75 mmol) is added in one portionsodium methoxide powder (776 mg, 13.6 mmol) at RT under an argonatmosphere. The reaction mixture is stirred at RT overnight. Thereaction mixture is quenched with sat. aq. NH₄Cl (200 mL) and extractedtwice with DCM (2×250 mL). The combined organic extracts are dried overMgSO₄, filtered and concentrated in vacuo. The crude is purified byprep. LC-MS in basic conditions. LC-MS method A: t_(R)=0.98 Min;[M+H]⁺=480.13.

8.01c(3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

To a solution of(3S,4S)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester (1000 mg, 2.09 mmol) in THF (30mL) is added 1 M NaOH (7 mL, 6.26 mmol). The mixture is stirred 4 h atRT. 2 M HCl (3.7 mL, 6.47 mmol, 3.1 eq) is added to reach pH 3 and THFis evaporated until dryness. The white solid is dried under high vacuumovernight. LC-MS method A: t_(R)=0.85 min; [M+H]⁺=451.8.

8.01d:(3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

A solution of(3S,4S)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester (500 mg, 1.11 mmol) in DMF (12 mL) is treatedwith 1-(pyridin-2-yl)cyclopropan-1-amine dihydrochloride (226 mg, 1.11mmol), DIPEA (1.01 mL, 5.76 mmol) and HATU (5.35 mg, 1.33 mmol). Themixture is stirred 2 h at RT. Saturated NaHCO₃ solution (20 mL) and DCM(20 mL) are added and the aq. phase is extracted twice with DCM (2×20mL), dried over MgSO₄, filtered and evaporated. The crude is purified byPrep HPLC using basic conditions. The title compound is obtained as awhite solid. LC-MS method A: t_(R)=0.77 Min; [M+H]⁺=568.29.

8.01:(3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide hydrochloride

(3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester (205 mg, 0.361 mmol) is dissolved in dioxane (8mL) at RT. A 4M solution of HCl in dioxane (1 mL, 4 mmol) is added andthe reaction stirred at RT for 1 h. The reaction mixture isconcentrated. The white solid is dried under high vacuum overnight LC-MSA: t_(R)=0.50 min; [M+H]⁺=467.83.

BB 8.02:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide hydrochoride 8.02a:(3R,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

The title compound is prepared by treatment of(3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-ethyl ester and 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic acidlithium salt according to procedure 8.01a. LC-MS method A: t_(R)=1.07Min; [M+H]⁺=480.16.

8.02b:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester 3-ethyl ester

The title compound is prepared according to the procedure 8.01b,starting from building block 8.02a; LC-MS method A: t_(R)=1.04 Min;[M+H]⁺=480.16.

8.02c(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

The title compound is prepared according to the procedure 8.01c,starting from building block 8.02b; LC-MS method A: t_(R)=0.91 min;[M+H]⁺=452.18.

8.02d:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 8.01d,starting from 8.02c and 1-(pyrimidin-2-yl)cyclopropan-1-aminehydrochloride; LC-MS method A: t_(R)=0.93 Min; [M+H]⁺=569.24.

8.02:(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide hydrochoride

The title compound is prepared according to the procedure 8.01 describedabove, starting from building block 2.04c; LC-MS method A: t_(R)=0.62min; [M+H]⁺=469.16.

Buildings Blocks Preparation of Amines of Structure 2

BB-9.01 1-(1-Oxy-pyrimidin-2-yl)-cyclopropylamine hydrochoride 9.01a:[1-(1-Oxy-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester

To a solution of (1-Pyrimidin-2-yl-cyclopropyl)-carbamic acid tert-butylester (200 mg, 0.834 mmol) in DCM (5 mL) at 0° C. is added portionwise3-chloroperbenzoic acid (226 mg, 0.917 mmol). The reaction mixture isstirred at RT for 72 h. The mixture is diluted with DCM (20 mL) andwashed with aq. sat. NaHCO₃(20 mL). The organic phase is separated andthe aq. phase is extracted with DCM (20 mL), The combined organic aredried over MgSO₄, filtered and concentrated. The crude is purified byPrep HPLC using basic conditions. The title compound is obtained as awhite solid. LC-MS method A: t_(R)=0.77 Min; [M+H]⁺=568.29. to give thetittle compound as a yellowish powder; LC-MS method A: t_(R)=0.60 min;[M+H]⁺=252.27.

9.01: 1-(1-Oxy-pyrimidin-2-yl)-cyclopropylamine hydrochloride

[1-(1-Oxy-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester(74 mg, 0.29 mmol) is dissolved in MeOH (3 mL) at RT. A 4M solution ofHCl in dioxane (0.44 mL, 1.77 mmol) is added and the reaction mixture isstirred at RT for 18 h. The solvents are evaporated to give the titlecompound as a yellowish solid; LC-MS method A: t_(R)=0.21 min;[M+H]⁺=152.31.

REFERENCE EXAMPLES Reference Example 1rac-(3R*,4R*)-4-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide

The title compound is prepared according to the procedure described forthe preparation of Example 7.001 starting from building block 7.02 and5-cyclopropyl-isoxazole-3-carboxylic acid. LC-MS method A: t_(R)=0.61Min; [M+H]⁺=451.27.

Chiral preparative SFC ofrac-(3R*,4R*)-4-[(5-cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide using a column ChiralPak IC, 5μm, 4.6×250 mm; with a mixture of A (CO₂) and B (DCM/MeOH/DEA 50:50:01))as eluent yields both enantiomers:

Reference Compound 1a:(3R,4R)-4-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide or(3S,4S)-4-[(5-cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

Chiral HPLC t_(R)=1.80 min.; QC LC-MS method: t_(R)=0.5 min; [M+H]⁺=451;IC₅₀: >10000 nM.

Reference Compound 1 b:(3R,4R)-4-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide or(3S,4S)-4-[(5-cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

Chiral HPLC t_(R)=2.48 min.; QC LC-MS method: t_(R)=0.5 min;[M+H]⁺=451.3;

IC₅₀: >10000 nM.

Reference Example 2(3R,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide and(3S,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide Step 1:rac-(3R*,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylicacid 1-tert-butyl ester

The title compound is prepared according to the procedure 2.01c,starting from building block 6.01c by treatment with NaOH in THF/H₂O,followed by aq. HCl; LC-MS method A: t_(R)=1.01 min; [M+H]⁺=452.22.

Step 2:rac-(3R*,4S1-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared according to the procedure 2.01d,starting from step 1 and 1-(pyrimidin-2-yl)cyclopropan-1-aminehydrochloride; LC-MS method A: t_(R)=1.06 min; [M+H]⁺=569.33.

Step 3:rac-(3R*,4S1-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

The title compound is prepared according to the procedure 2.01, startingfrom step 2; LC-MS method A: t_(R)=0.74 min; [M+H]⁺=469.14.

Step 4:rac-(3R*,4S1-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

The title compound is prepared according to the method D, starting fromstep 3; LC-MS method A: t_(R)=0.71 min; [M+H]⁺=523.18.

Chiral preparative HPLC ofrac-(3R*,4S1-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide using a column ChiralPak IC, 5μm, 4.6×250 mm; with a mixture of A (10% Heptan, 0.05% DEA)) and B (90%EtOH, 0.05% DEA) as eluent and a flow of 1.2 mL/min. Chiral HPLC: yieldsboth enantiomers:

Reference Example 2a:(3R,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

Chiral HPLC t_(R)=12.01 min.; QC LC-MS method: t_(R)=0.7 min;[M+H]⁺=523.1;

IC₅₀: >10000 nM.

Reference Example 2b:(3S,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

Chiral HPLC t_(R)=18.35 min.; QC LC-MS method: t_(R)=0.7 min;[M+H]⁺=523.4;

IC₅₀: 2250 nM.

Reference Example 3(3S,4S)-1-Cyclopropylmethyl-4-[(5-phenyl-isoxazole-3-carbonyl)-amino]-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide

Reference example 3 is prepared according to example 7.001, startingfrom (3S,4S)-4-amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid(1-pyrimidin-2-yl-cyclopropyl)-amide and 4-phenyl-isoxazole-3-carboxylicacid. LC-MS method A: t_(R)=0.66 min; [M+H]⁺=487.13.

IC₅₀: 1330 nM.

Table 6 summarizes NMR characterization data of particular examplecompounds.

TABLE 6 ¹H NMR data of particular example compounds Example Chemicalshift (δ) in part per million (ppm) Solvent 1.004 (400 MHz) δ: 8.72 (d,J = 8.6 Hz, 1H), 8.08-8.01 (m, 1H), 7.60-7.54 (m, 1H), DMSO-d6 7.36-7.30(m, 1H), 7.08 (d, J = 2.7 Hz, 1H), 4.10-4.05 (m, 1H), 3.78-3.72 (m, 2H),3.22-3.15 (m, 1H), 2.93-2.81 (m, 4H), 2.29-2.19 (m, 3H), 1.90-1.68 (m,9H), 1.61-1.54 (m, 2H), 1.20-1.15 (m, 5H). 1.095 (400 MHz) δ: 8.93 (s,1H), 8.54 (d, J = 8.6 Hz, 1H), 7.94-7.86 (m, 1H), DMSO-d6 7.71-7.64 (m,1H), 7.39-7.33 (m, 1H), 4.15-4.05 (m, 1H), 3.25-3.17 (m, 1H), 3.07 (s,3H), 2.88-2.81 (m, 2H), 2.75 (s, 3H), 2.32-2.16 (m, 3H), 1.80-1.72 (m,5H), 1.63-1.55 (m, 2H), 1.18-1.14 (m, 5H). 1.107 (400 MHz) δ: 8.80 (d, J= 8.8 Hz, 1H), 7.51 (dd, J = 9.2, 9.2 Hz, 2H), DMSO-d6 7.15 (s, 1H),4.38-4.31 (m, 1H), 4.17-4.11 (m, 1H), 4.05-3.91 (m, 1H), 3.83-3.69 (m,2H), 3.02-2.96 (m, 2H), 2.77-2.68 (m, 1H), 2.27 (dd, J = 6.4, 12.7 Hz,1H), 2.19-1.98 (m, 5H), 1.83-1.76 (m, 1H), 1.69-1.59 (m, 1H), 0.83 (dd,J = 6.2, 6.2 Hz, 1H), 0.48-0.44 (m, 2H), 0.10-0.05 (m, 2H). 1.113b (400MHz) δ: 8.57 (d, J = 8.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.14 (d, J = 1.2Hz, 2H), DMSO-d6 3.95-3.87 (m, 2H), 3.12 (s, 3H), 2.97 (d, J = 11.2 Hz,2H), 2.62-2.54 (m, 1H), 2.21-2.17 (m, 2H), 2.13-1.95 (m, 2H), 1.82 (dd,J = 3.4, 13.0 Hz, 1H), 1.57-1.48 (m, 1H), 1.11 (s, J = 5.1 Hz, 6H),0.87-0.77 (m, 1H), 0.45 (d, J = 7.1 Hz, 2H), 0.09-0.05 (m, 2H). 1.118a(400 MHz) δ: 8.99 (s, 1H), 8.57-8.47 (m, 2H), 8.22 (d, J = 8.1 Hz, 1H),7.94-7.87 (m, DMSO-d6 1H), 7.72-7.64 (m, 2H), 7.39-7.35 (m, 1H),7.31-7.22 (m, 2H), 4.93-4.87 (m, 1H), 4.06-4.01 (m, 1H), 2.95-2.91 (m,2H), 2.80-2.73 (m, 1H), 2.15-1.97 (m, 2H), 1.88-1.74 (m, 2H), 1.59-1.45(m, 5H), 1.34-1.27 (m, 2H), 1.23 (s, 1H), 1.17-1.13 (m, 3H). 1.189 (400MHz) δ: 8.43-8.51 (m, 4 H), 7.99 (s, 1 H), 7.97 (s, 1 H), 7.92 (d, J =2.1 Hz, DMSO-d6 1 H), 7.66 (dd, J₁ = 2.2 Hz, J₂ = 8.5 Hz, 1 H), 7.38 (s,1 H), 7.18 (t, J = 4.9 Hz, 1 H), 3.99 (m, 1H), 2.70-3.18 (m, 3 H),1.80-2.23 (m, 6 H), 1.48 (d, J = 3.8 Hz, 1 H), 1.36-1.40 (m, 2 H), 1.16(m, 1 H), 0.83 (m, 1H) 0.49-0.50 (m, 2 H), 0.10 (d, J = 0.7 Hz, 2 H).2.019a (400 MHz) δ: 8.72 (d, J = 8.6 Hz, 1H), 8.07-8.00 (m, 1H),7.58-7.51 (m, 1H), DMSO-d6 7.35-7.29 (m, 1H), 7.08 (d, J = 2.9 Hz, 1H),4.14-4.05 (m, 1H), 3.19-3.15 (m, 1H), 3.05 (s, 3H), 2.98-2.92 (m, 2H),2.76 (s, 3H), 2.51 (s, 1H), 2.00-1.92 (m, 2H), 1.80-1.76 (m, 3H),1.62-1.59 (m, 3H), 1.48 (t, J = 5.5 Hz, 2H), 1.38-1.29 (m, 2H). 2.031(400 MHz) δ: 8.73 (d, J = 8.6 Hz, 1H), 8.08-8.01 (m, 1H), 7.60-7.53 (m,1H), DMSO-d6 7.36-7.30 (m, 1H), 7.09 (d, J = 2.9 Hz, 1H), 4.11-4.04 (m,1H), 3.20-3.14 (m, 2H), 3.06 (s, 3 H), 2.82-2.80 (m, 1H), 2.76 (s, 3H),2.71-2.63 (m, 1H), 1.88-1.53 (m, 8H), 1.08 (d, J = 19.3 Hz, 6H). 2.073(400 MHz) δ: 8.49-8.55 (m, 3 H), 8.44 (s, 1 H), 8.05-8.09 (m, 1 H), 7.62(d, J = 2.5 Hz, DMSO-d6 1 H), 7.57-7.60 (m, 1 H), 7.32-7.37 (m, 1 H),7.16-7.19 (m, 2 H), 3.96 (dd, J₁ = 4.2 Hz, J₂ = 8.5 Hz, 1 H), 2.92 (d, J= 9.7 Hz, 1 H), 2.74-2.80 (m, 2 H), 2.62-2.68 (m, 1 H), 2.32 (m, 1 H),2.29 (s, 1 H), 2.17-2.19 (m, 1 H), 1.85-1.89 (m, 1 H), 1.46-1.56 (m, 1H), 1.36-1.40 (m, 1 H), 1.09 (m, 2 H), 0.99 (d, J = 6.5 Hz, 6 H). 2.074(400 MHz) □: 8.57 (d, J = 8.5 Hz, 1 H), 8.45-8.50 (m, 3 H), 8.08 (m, 1H), 7.60 (m, 1 DMSO-d6 H), 7.34 (td, J₁ = 2.2 Hz, J₂ = 8.5 Hz, 1 H),7.16-7.19 (m, 2 H), 3.98 (dd, J₁ = 3.6 Hz, J₂ = 8.1 Hz, 1 H), 2.92 (d, J= 9.1 Hz, 1 H), 2.63-2.82 (m, 3 H), 1.74-1.99 (m, 7 H), 1.46-1.65 (m, 4H), 1.35-1.39 (m, 1 H), 1.06-1.10 (m, 2 H). 3.003b (500 MHz) δ: 9.26 (d,J = 8.5 Hz, 1 H), 8.18-8.13 (m, 1 H), 7.64 (m, 1 H), 7.39 (td, J₁ =DMSO-d6 8.3 Hz, J₂ = 2.1 Hz, 1 H), 4.10 (m, 1 H), 3.21-3.15 (m, 1 H),3.07 (s, 3 H), 2.90-2.78 (m, 2 H), 2.76 (s, 3 H), 2.38-2.25 (m, 2 H),2.17 (t, J = 11.2 Hz, 1 H), 1.85-1.82 (m, 1 H), 1.76-1.68 (m, 4 H),1.63-1.56 (m, 2 H), 1.30-1.15 (m, 4 H), 1.07 (m, 1 H). 3.015 (400 MHz)δ: 8.98 (d, J = 8.8 Hz, 1 H), 8.56 (s, 1 H), 8.32 (d, J = 4.6 Hz, 1 H),DMSO-d6 7.99-7.93 (m, 1 H), 7.78 (d, J = 3.3 Hz, 1 H), 7.52 (m, 1 H),7.34-7.20 (m, 3 H), 7.01-6.98 (m, 1 H), 4.05-4.02 (m, 1 H), 3.11-3.01(m, 2 H), 2.86-2.80 (m, 1 H), 2.51 (s), 2.29-2.01 (m, 4 H), 1.85-1.82(m, 1 H), 1.68-1.64 (m, 1 H), 1.49-1.44 (m, 1 H), 1.31 (m, 1 H),0.87-0.82 (m, 1 H), 0.48 (m, 2 H), 0.09 (m, 2 H). 3.019 (400 MHz) δ:9.35 (d, J = 8.3 Hz, 1H), 8.15-8.07 (m, 1H), 7.60-7.53 (m, DMSO-d6 1H),7.39-7.33 (m, 1H), 4.15-4.04 (m, 1H), 3.06 (s, 3H), 2.93-2.80 (m, 3H),2.77 (s, 3H), 2.34-2.12 (m, 3H), 1.87-1.81 (m, 1H), 1.76-1.72 (m, 4H),1.65-1.52 (m, 2H), 1.24-1.18 (m, 4H), 1.14-1.04 (m, 1H). 4.005 (400 MHz)δ: 8.70 (d, J = 8.5 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 H), 7.58-7.56 (m, 1H), DMSO-d6 7.33 (td, J₁ = 8.5 Hz, J₂ = 1.9 Hz, 1 H), 7.09 (d, J = 2.8Hz, 1 H), 4.12-4.03 (m, 1 H), 3.13 (td, J₁ = 10.7 Hz, J₂ = 3.3 Hz, 1 H),3.06 (s, 3 H), 2.88-2.77 (m, 5 H), 2-38-2.12 (m, 2 H), 1.83 (dd, J₁ =12.5 Hz, J₂ = 3.9 Hz, 1 H), 1.73 (d, J = 7.3 Hz, 4 H), 1.57 (m, 2 H),1.25-1.02 (m, 6 H). 4.032 (400 MHz) δ: 8.57 (d, J = 8.5 Hz, 1 H), 8.51(d, J = 4.8 Hz, 2 H), 8.47 (s, 1 H), DMSO-d6 8.05-8.11 (m, 1 H),7.59-7.62 (m, 1 H), 7.35 (m, 1 H), 7.14-7.21 (m, 2 H), 3.94-4.04 (m, 1H), 3.32-3.40 (m, 1 H), 3.13-3.19 (m, 1 H), 2.95-3.03 (m, 1 H),2.67-2.77 (m, 1 H), 2.45-2.60 (m, 19 H), 2.16-2.27 (m, 2 H), 2.09-2.14(m, 1 H), 1.98-2.04 (m, 1 H), 1.84-1.90 (m, 1 H), 1.55-1.66 (m, 1 H),1.48-1.52 (m, 1 H), 1.35-1.40 (m, 1 H), 1.04-1.14 (m, 2 H), 0.81-0.89(m, 1 H), 0.45-0.52 (m, 2 H), 0.04-0.14 (m, 2 H) 4.033 (400 MHz) δ: 8.76(d, J = 8.6 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.09-8.02 (m, 2H),DMSO-d6 7.59-7.51 (m, 1H), 7.40-7.29 (m, 3H), 7.15-7.06 (m, 2H),3.99-3.89 (m, 1H), 3.07-2.99 (m, 2H), 2.81-2.73 (m, 1H), 2.24-2.16 (m,2H), 2.12-1.98 (m, 2H), 1.88-1.82 (m, 1H), 1.62-1.55 (m, 1H), 1.51 (s,3H), 1.43 (s, 3H), 0.86-0.82 (m, 1H), 0.51-0.45 (m, 2H), 0.10-0.05 (m,2H). 4.052 (400 MHz) δ: 8.57 (d, J = 8.5 Hz, 1 H), 8.48-8.51 (m, 3 H),8.08 (m, 1 5H), 7.59 (m, 1 DMSO-d6 H), 7.34 (m, 1 H), 7.16-7.20 (m, 2H), 4.00 (d, J = 11.8 Hz, 1 H), 3.15-3.18 (m, 1 H), 3.00-3.03 (m, 1 H),2.72-2.78 (m, 3 H), 2.32 (d, J = 11.6 Hz, 1 H), 2.21 (m, 1 H), 1.84-1.87(m, 1 H), 1.62-1.65 (m, 1 H), 1.49 (d, J = 6.0 Hz, 1 H), 1.35-1.39 (m, 1H), 0.99-1.10 (m, 4 H), 0.66-0.70 (m, 2 H). 4.055 (400 MHz) δ: 8.94-9.02(m, 2 H), 8.81 (d, J = 0.7 Hz, 1 H), 8.34 (m, 1 H), DMSO-d6 8.09-8.14(m, 2 H), 7.59-7.60 (m, 1 H), 7.26-7.37 (m, 3 H), 4.18 (s, 1 H),3.26-3.46 (m, 7 H), 1.96-1.98 (m, 1 H), 1.47-1.52 (m, 2 H), 1.15-1.19(m, 2 H), 1.00-1.03 (m, 1 H), 0.56-0.58 (m, 2 H), 0.25-0.25 (m, 2 H).4.081 (400 MHz) δ: 8.88 (s, 1 H), 8.73 (d, J = 8.6 Hz, 1 H), 8.58 (s, 1H), 8.48 (s, 2 H), DMSO-d6 8.06-8.12 (m, 1 H), 7.57-7.63 (m, 1 H), 7.35(td, J₁ = 2.0 Hz, J₂ = 8.3 Hz, 1 H), 7.12 (d, J = 3.0 Hz, 1 H),4.00-4.03 (m, 1 H), 3.34 (s, 4 H), 2.99-3.08 (m, 2 H), 2.68-2.72 (m, 1H), 2.01-2.25 (m, 4 H), 1.81-1.85 (m, 1 H), 1.61-1.62 (m, 1 H),1.05-1.30 (m, 1 H), 0.74-0.86 (m, 3 H), 0.47 (d, J = 7.8 Hz, 2 H), 0.08(s, 2 H) 4.101 (400 MHz) δ: 8.54 (d, J = 8.0 Hz, 1 H), 8.50 (d, J = 4.7Hz, 2 H), 8.47 (s, 1 H), DMSO-d6 8.05-8.11 (m, 1 H), 7.57-7.63 (m, 1 H),7.32-7.36 (m, 1 H), 7.17 (m, 2 H), 3.90-4.00 (m, 1 H), 3.30-3.38 (m, 3H), 3.12-3.18 (m, 1 H), 2.97-3.03 (m, 1 H), 2.68 (ddd, J₁ = 2.5 Hz, J₂ =6.3 Hz, 1 H), 2.51 (s, 46 H), 2.18-2.23 (m, 1 H), 2.08-2.14 (m, 1 H),1.86-1.93 (m, 1 H), 1.47-1.57 (m, 2 H), 1.36-1.40 (m, 1 H), 1.05-1.15(m, 11 H) 4.102 (400 MHz) δ: 8.59-8.63 (m, 3 H), 8.04-8.10 (m, 2 H),7.61 (d, J = 2.5 Hz, 1 H), DMSO-d6 7.56-7.59 (m, 1 H), 7.31-7.35 (m, 1H), 7.25 (t, J = 4.8 Hz, 1 H), 7.16 (d, J = 3.0 Hz, 1 H), 3.87 (d, J =11.9 Hz, 1 H), 3.34 (s, 2 H), 2.96-3.01 (m, 1 H), 2.67-2.71 (m, 2 H),2.19 (d, J = 5.8 Hz, 2 H), 1.97-2.05 (m, 1 H), 1.82-1.86 (m, 1 H),1.51-1.58 (m, 6 H), 0.81-0.83 (m, 1 H), 0.45-0.48 (m, 2 H), 0.07 (q, J =4.7 Hz, 2 H)

II. Biological Assays In Vitro Assay

The antagonistic effect of the compounds of formula (I) on the CXCR7receptor are determined in accordance with the following experimentalmethod.

The assay is using the Tango CXCR7-bla U2OS cell line from invitrogen.These cells contain the human chemokine receptor CXCR7 linked to a TEVprotease site and a Gal4-VP16 transcription factor stably integratedinto the Tango GPCR-bla U2OS parental cell line. This parental cell linestably express a beta-arrestin/TEV protease fusion protein and thebeta-lactamase reporter gene under the control of a UAS responseelement. Upon ligand binding and receptor activation, theprotease-tagged beta-arrestin molecule is recruited to CXCR7 which islinked at the C-terminus by a protease cleavage site to a transcriptionfactor. The protease cleaves the transcription factor from CXCR7, whichtranslocates to the nucleus and activates the expression ofbeta-lactamase. A FRET-enabled substrate allows to detect beta-lactamaseexpression.

Tango CXCR7-bla U2OS cells are detached from culture dishes with 0.05%trypsin-EDTA and collected in growing medium (McCoy's 5A 90% (v/v),dialyzed FCS 10% (v/v), 0.1 mM NEAA, 25 mM HEPES (pH7.3), 1 mM sodiumpyruvate, P/S 1% (v/v) 50 μg/ml Hygromycin, 100 μg/ml Geneticin, 200μg/ml Zeocin), spinned down and resuspended in assay medium (McCoy's 5A90% (v/v), dialyzed FCS 1% (v/v), 0.1 mM NEAA, 25 mM HEPES (pH7.3), P/S1% (v/v)). 10′000 cells per well (in 30 μl) are seeded in a 384 wellplate (black-walled, clear bottom). The plate is incubated at 37° C./5%CO₂ for 24 hours. Test compounds are dissolved to 10 mM in DMSO andserially diluted in DMSO to 500× of the final concentration for doseresponse curves. Compounds are then diluted 1:100 in assay medium to 5×of the final concentration. 10 μl/well of diluted compounds are added tothe assay plate and incubated for 15 minutes at 37° C. ThereafterCXCL12/SDF1-0c is diluted in assay medium to 5× of the finalconcentration (its EC80 value for receptor activation) and 10 μl/wellare added to the assay plate. The agonist leads to activation of thereceptor and therefore to b-arrestin recruitment. Compounds acting asantagonists reduce this activation. The plate is incubated for 22 hrs at37° C. 10 μl/well of detection reagent (LiveBLAzer™-FRET B/G (CCF4-AM)substrate) is transferred to the assay plate and the plate is incubatedfor 2 hours at room temperature protected from light. Fluorescent countsare determined (Scan1: Ex 409/20 nm, Em 460/30 nm, Scan 2: Ex 409/20 nm,Em 530/30 nm). The calculated emission ratio is used for IC50determination. The calculated IC₅₀ values may fluctuate depending on thedaily cellular assay performance. Fluctuations of this kind are known tothose skilled in the art. Average IC₅₀ values from several measurementsare given as geometric mean values.

TABLE 7 Example IC₅₀ Nr [nmol/l] 1.001 1 1.001a 0.3 1.001b 302 1.002 21.002a 359 1.002b 1 1.003 564 1.004 764 1.005 198 1.006 414 1.007 7801.008 394 1.009 66 1.01 82 1.011 282 1.012 58 1.013 238 1.014 289 1.015429 1.016 275 1.017 489 1.018 317 1.019 145 1.02 198 1.021 282 1.022 1981.023 743 1.024 118 1.025 51 1.026 627 1.027 117 1.028 916 1.029 3151.03 201 1.031 855 1.032 154 1.033 591 1.034 772 1.035 520 1.036 6931.037 295 1.038 490 1.039 492 1.04 7 1.041 91 1.042 532 1.043 843 1.044556 1.045 565 1.046a 474 1.047 127 1.048 275 1.049 10 1.05 223 1.051 491.052 630 1.053 703 1.054 311 1.055 232 1.056 4 1.057 1 1.058 1 1.059140 1.06 727 1.061 49 1.062 16 1.063 107 1.064 968 1.065 567 1.066 161.067 319 1.068 512 1.069 556 1.07 559 1.071 4 1.072 32 1.073 118 1.0749 1.075 44 1.076 604 1.077 443 1.078 193 1.079 510 1.08 564 1.081 1181.082 445 1.083 76 1.084 223 1.085 268 1.086 154 1.087 943 1.088 2441.089 472 1.09 35 1.091 103 1.092 1 1.093 867 1.094 100 1.095 254 1.095a129 1.096 667 1.097 442 1.098 276 1.099 131 1.1 128 1.101 45 1.102 1111.103 274 1.104 964 1.105 430 1.106 248 1.107 520 1.108 581 1.109 9021.11 535 1.111 332 1.111a 944 1.111b 114 1.112 227 1.113 118 1.113a 5611.113b 48 1.114 626 1.115 566 1.116 614 1.117 68 1.117a 39 1.118 361.118a 75 1.119 146 1.12 789 1.121 4 1.121a 742 1.121b 2 1.122 10 1.122a525 1.122b 17 1.123 15 1.123a 4 1.124 16 1.125 81 1.125a 30 1.126 491.127 360 1.128 124 1.129 105 1.129a 647 1.129b 35 1.13 140 1.131 1021.132 410 1.133 594 1.134 266 1.135 592 1.136 202 1.137 919 1.138 8161.138a 437 1.138b 83 1.139 50 1.139a 790 1.139b 29 1.14 358 1.141 3791.142 472 1.143 719 1.144 178 1.145 363 1.146 904 1.147 443 1.148 7691.149 276 1.15 155 1.151 554 1.152 569 1.153 803 1.154 54 1.154a 461.155 315 1.156 92 1.156a 19 1.157 131 1.158 82 1.159 818 1.16 526 1.161105 1.162 638 1.163 953 1.164 267 1.165 92 1.165a 43 1.165b 537 1.166 521.167 134 1.168 728 1.169 5 1.17 16 1.170a 33 1.171 16 1.171a 7 1.171b446 1.172 72 1.173 110 1.174 36 1.175 673 1.176 6 1.176a 5 1.177 5 1.1787 1.179 50 1.18 235 1.181 104 1.182 218 1.183 79 1.184 3 1.185 9 1.18637 1.187a 410 1.187b 981 1.187c 3 1.187d 353 1.188a 3 1.188b 519 1.188c179 1.188d 362 1.189 36 1.189a 15 1.19 294 1.191 186 1.192 389 1.192a854 1.192b 122 1.193 191 1.193a 97 1.194a 13 1.195 759 1.196 575 1.19711 1.198 52 1.199 273 2.001 209 2.002 670 2.003 34 2.004 118 2.005 252.006 15 2.007 88 2.008 405 2.009 10 2.01 42 2.011 114 2.013 28 2.014269 2.015 54 2.016 80 2.016a 49 2.016b 63 2.017 73 2.018 145 2.019 1262.019a 44 2.02 248 2.021 293 2.022 155 2.023 37 2.023a 9 2.023b 26 2.024101 2.025 435 2.026 249 2.027 745 2.028 60 2.029 60 2.03 74 2.031 5582.032 192 2.033 132 2.034 87 2.035 121 2.036 165 2.037 161 2.038 992.039 83 2.04 475 2.045 114 2.046 16 2.047 145 2.048 501 2.049 709 2.0515 2.051 42 2.052 267 2.053 26 2.054 138 2.055 49 2.056 48 2.057 502.058 347 2.059 169 2.06 4 2.061 41 2.062 23 2.062a 298 2.062b 14 2.063219 2.064 84 2.065 1 2.066 359 2.067 18 2.068 12 2.069 6 2.07 11 2.071 82.072 1 2.073 20 2.074 25 2.075 554 2.076 71 2.077 112 2.078 72 2.079 382.08 311 2.081 118 2.082 342 2.083 777 2.084 8 2.085 179 2.086 111 2.08784 2.088 45 2.089 975 2.09 3 2.091 62 2.092 95 2.093 26 2.094 2 2.095 182.096 634 2.097 650 2.098 94 2.099 343 2.1 396 2.101 29 2.102 411 2.1034 2.104 195 2.105 60 2.106 13 2.107 114 2.108 3 3.001 965 3.002 4353.003 105 3.003a 771 3.003b 54 3.004 338 3.005 38 3.006 108 3.007 1623.009 286 3.01 69 3.011 22 3.012 26 3.013 153 3.014 158 3.015 170 3.016105 3.016a 90 3.017 661 3.018 198 3.019 778 3.020a 271 3.020b 4 3.021 403.022 28 3.022a 25 4.001 133 4.002 60 4.003 333 4.004 319 4.005 3884.006 149 4.007 52 4.008 150 4.009 573 4.01 6 4.011 43 4.012 49 4.013145 4.014 363 4.015 783 4.016 463 4.017 114 4.018 343 4.019 151 4.02 2224.021 126 4.022 369 4.023 69 4.024 56 4.025 439 4.026 15 4.027 8 4.02832 4.029 2 4.03 1 4.031 4 4.032 3 4.033 0.3 4.034 255 4.035 56 4.036 1274.037 280 4.038 522 4.039 393 4.04 86 4.041 96 4.042 74 4.043 158 4.04475 4.045 164 4.046 290 4.047 318 4.048 247 4.049 148 4.05 21 4.051 3564.052 24 4.053 1 4.054 1 4.055 16 4.056 64 4.057 13 4.058 90 4.059 614.06 60 4.061 1 4.062 141 4.063 142 4.064 753 4.065 14 4.066 320 4.067a20 4.067b 2 4.068 1 4.069 153 4.07 73 4.071 212 4.072 16 4.072a 8 4.073173 4.074 27 4.075 2 4.076 97 4.077 4 4.078 64 4.078b 15 4.079a 1864.079b 18 4.08 46 4.080a 851 4.080b 15 4.081 426 4.082 20 4.083 11 4.084232 4.084b 77 4.085 61 4.086 472 4.087 342 4.088 138 4.089 299 4.09 344.091 134 4.092 126 4.093 165 4.094 201 4.095 57 4.096 33 4.097 80 4.09818 4.098a 12 4.099 852 4.1 159 4.101 71 4.101a 18 4.101b 712 4.102 15.001 368 5.002 857 7.001 32 7.002 308 7.003 210 7.004 64 7.005 36 7.0068 7.007 140 7.008 51 7.009 240 7.01 60 7.011 78 7.012 356 7.013 2527.014 629 7.015 201 7.016 2 BB 1.01c 206 BB 1.18c 119

Compounds of the present invention may be further characterized withregard to their general pharmacokinetic and pharmacological propertiesusing conventional assays well known in the art; for example relating totheir bioavailablility in different species (such as rat or dog); or fortheir properties with regard to drug safety and/or toxicologicalproperties using conventional assays well known in the art, for examplerelating to cytochrome P450 enzyme inhibition and time dependentinhibition, pregnane X receptor (PXR) activation, glutathione binding,or phototoxic behavior.

1. A compound of formula (I_(A))

wherein the two substituents of the piperidine ring: R¹—CO— and—NH—CO—Ar¹—Ar², are in relative trans-configuration; Ar¹ represents a5-membered heteroarylene group selected from oxazol-diyl, isoxazol-diyl,oxadiazol-diyl, or triazol-diyl, wherein the —NH—CO— group and Ar² areattached in meta arrangement to ring atoms of Ar¹; wherein said5-membered heteroarylene is unsubstituted, or mono-substituted withR^(Ar1); wherein R^(Ar1) represents methyl, methoxy, fluorine, chlorine,trifluormethyl, or trifluoromethoxy; Ar² represents phenyl, or6-membered heteroaryl; wherein said phenyl or 6-membered heteroarylindependently is mono-, di- or tri-substituted, wherein the substituentsare independently selected from fluoro, chloro, methyl, cyano, methoxy,or (C₁)fluoroalkyl; R¹ represents R^(N1)R^(N2)N_, wherein R^(N1)represents hydrogen; (C₁₋₆)alkyl; (C₁₋₆)alkyl which is mono-substitutedwith hydroxy; (C₁₋₃)alkoxy; 2-hydroxy-ethoxy; —CO—NH₂; —SO₂—(C₁₋₃)alkyl;cyano; (C₁₋₃)fluoroalkoxy; —NR^(N3)R^(N4), wherein R^(N3) and R^(N4)independently represent hydrogen or (C₁₋₄)alkyl; (C₂₋₆)alkynyl;(C₂₋₅)fluoroalkyl; (C₁₋₄)alkoxy; 2-(2-oxo-pyrrolidin-1-yl)-ethyl; agroup -L¹-Cy¹; wherein L¹ represents a direct bond, —(C₁₋₃)alkylene-, or—(C₃₋₅)cycloalkylene-; and Cy¹ represents (C₃₋₆)cycloalkyl, wherein said(C₃₋₆)cycloalkyl optionally contains one ring oxygen atom; wherein said(C₃₋₆)cycloalkyl independently is unsubstituted; or mono-substitutedwith fluoro, methyl, or hydroxy, —CO—(C₁₋₄)alkoxy, or cyano; ordi-substituted with fluoro, or tri-substituted with methyl and twofluoro; a group -L²-Ar³, wherein L² represents a direct bond,—(C₁₋₄)alkylene-; *—(C₃₋₅)cycloalkylene-(C₀₋₂)alkylene- wherein said(C₃₋₅)cycloalkylene optionally contains one ring oxygen atom, whereinthe asterisk indicates the bond to which Ar³ is attached;*—(C₁₋₂)alkylene-(C₃₋₅)cycloalkylene- wherein said (C₃₋₅)cycloalkyleneoptionally contains one ring oxygen atom, wherein the asterisk indicatesthe bond to which Ar³ is attached; or —(C₁₋₃)alkylene- which ismono-substituted with hydroxy, trifluoromethyl, or —CO—(C₁₋₄)alkoxy; andAr³ represents phenyl, or 5- or 6-membered heteroaryl; wherein saidphenyl or 5- or 6-membered heteroaryl independently is unsubstituted, ormono-, or di-substituted; wherein the substituents are independentlyselected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, hydroxy,(C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein, in case Ar³represents 6-membered heteroaryl which is pyridyl or pyrimidinyl, suchpyridyl or pyrimidinyl may additionally be present in form of therespective N-oxide; and R^(N2) independently represents hydrogen,(C₁₋₄)alkyl, or (C₂₋₃)fluoroalkyl; or R^(N1) and R^(N2) together withthe nitrogen atom to which they are attached to form a 4- to 6-memberedring selected from azetidinyl, pyrrolidinyl or piperidinyl; eachindependently unsubstituted; or mono-substituted with fluoro, methyl, orhydroxy; or di-substituted with fluoro; or mono-substituted with Ar⁴,wherein Ar⁴ represents phenyl, or 5- or 6-membered heteroaryl; whereinsaid phenyl or 5- or 6-membered heteroaryl independently isunsubstituted, or mono-, or di-substituted; wherein the substituents areindependently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; or morpholinyl; R² representshydrogen; (C₁₋₆)alkyl; (C₂₋₆)alkyl which is mono-substituted with(C₁₋₃)alkoxy, or hydroxy; (C₃₋₅)alkenyl (especially allyl);cyano-methyl; (C₂₋₃)fluoroalkyl; (C₃₋₈)cycloalkyl-(C₀₋₃)alkyl; whereinthe (C₃₋₈)cycloalkyl is unsubstituted, or mono- or di-substitutedwherein the substituents are independently selected from (C₁₋₃)alkyl,fluoro, hydroxy, hydroxy-(C₁₋₃)alkyl, (C₁₋₃)alkoxy, or(C₁₋₃)fluoroalkyl; thietan-3-yl; (C₃₋₈)cycloalkenyl-(C₁₋₃)alkyl; orAr⁵—CH₂-wherein Ar⁵ represents phenyl, or 5- or 6-membered heteroaryl,wherein the phenyl or 5- or 6-membered heteroaryl independently isunsubstituted, or mono- or di-substituted wherein the substituents areindependently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; and R³ represents hydrogen, ormethyl; or a pharmaceutically acceptable salt thereof.
 2. The compoundof formula (Ia) as defined claim 1 which are also compounds of Formula(Ia_(S)), wherein the two substituents of the piperidine ring: R¹—CO—and —NH—CO—Ar¹—Ar², are in relative trans-configuration, wherein theabsolute configuration of the two chiral carbon atoms in position 3 and4 of the piperidine ring is (3S,4S):

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 2; wherein R³ represents hydrogen; or a pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 3; whereinAr¹ represents oxazol-2,5-diyl, oxazol-2,4-diyl, isoxazol-3,5-diyl,[1,3,4]oxadiazol-2,5-diyl, [1,2,4]oxadiazol-3,5-diyl, or1H-[1,2,3]triazol-1,4-diyl; wherein said 5-membered heteroarylene isunsubstituted; or a pharmaceutically acceptable salt thereof.
 5. Thecompound according to claim 4; wherein Ar² represents phenyl which ismono-, di- or tri-substituted; wherein one or two of said substituentsis/are independently selected from fluoro, chloro, or methyl, and theremaining, if present, is/are fluoro; or a pharmaceutically acceptablesalt thereof.
 6. The compound according to claim 1; wherein R¹represents R^(N1)R^(N2)N—, wherein R^(N1) represents (C₁₋₆)alkyl;(C₁₋₆)alkyl which is mono-substituted with hydroxy; (C₁₋₃)alkoxy;2-hydroxy-ethoxy; —CO—NH₂; —SO₂—(C₁₋₃)alkyl; cyano; (C₁₋₃)fluoroalkoxy;—NR^(N3)R^(N4), wherein R^(N3) and R^(N4) independently representhydrogen or (C₁₋₄)alkyl; (C₂₋₆)alkynyl; (C₂₋₅)fluoroalkyl;2-(2-oxo-pyrrolidin-1-yl)-ethyl; a group -L¹-Cy¹; wherein L¹ representsa direct bond, —(C₁₋₃)alkylene-, or —(C₃₋₅)cycloalkylene-; and Cy¹represents (C₃₋₆)cycloalkyl, wherein said (C₃₋₆)cycloalkyl optionallycontains one ring oxygen atom; wherein said (C₃₋₆)cycloalkylindependently is unsubstituted: or mono-substituted with fluoro, methyl,hydroxy, CO—(C₁₋₄)alkoxy, or cyano; or di-substituted with fluoro, ortri-substituted with methyl and two fluoro; a group -L²-Ar³, wherein L²represents a —(C₁₋₄)alkylene-; —(C₃₋₅)cycloalkylene- wherein said(C₃₋₅)cycloalkylene optionally contains one ring oxygen atom;*—(C₃₋₅)cycloalkylene-(C₁₋₂)alkylene- wherein said (C₃₋₅)cycloalkyleneoptionally contains one ring oxygen atom, wherein the asterisk indicatesthe bond to which Ar³ is attached; *—(C₁₋₂)alkylene-(C₃₋₅)cycloalkylene-wherein said (C₃₋₅)cycloalkylene optionally contains one ring oxygenatom, wherein the asterisk indicates the bond to which Ar³ is attached;or *—(C₁₋₃)alkylene- which is mono-substituted with hydroxy ortrifluoromethyl; and Ar³ represents phenyl, or 5-membered heteroarylcontaining one oxygen atom and one or two nitrogen atoms, or 6-memberedheteroaryl containing one or two nitrogen atoms; wherein said phenyl or5- or 6-membered heteroaryl independently is unsubstituted, or mono-, ordi-substituted; wherein the substituents are independently selected from(C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy; wherein, in case Ar³ represents 6-memberedheteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinylmay additionally be present in form of the respective N-oxide; andR^(N2) independently represents hydrogen, or (C₁₋₄)alkyl; or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1; wherein R¹ represents R^(N1)R^(N2)N—, wherein R^(N1) represents(C₃₋₆)cycloalkyl, wherein said (C₃₋₆)cycloalkyl optionally contains onering oxygen atom; wherein said (C₃₋₆)cycloalkyl independently isunsubstituted, or mono-substituted with fluoro, methyl, or hydroxy, ordi-substituted with fluoro, or tri-substituted with methyl and twofluoro; (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene-, wherein said (C₃₋₆)cycloalkyloptionally contains one ring oxygen atom;(C₃₋₆)cycloalkyl-(C₃₋₅)cycloalkylene-; phenyl-(C₁₋₄)alkylene- whereinsaid phenyl is unsubstituted, or mono-, or di-substituted; wherein thesubstituents are independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;phenyl-(C₁₋₃)alkylene- wherein said —(C₁₋₃)alkylene- is mono-substitutedwith hydroxy; phenyl-(C₃₋₅)cycloalkylene-; wherein said(C₃₋₅)cycloalkylene optionally contains one ring oxygen atom, andwherein said phenyl is unsubstituted, or mono-, or di-substituted;wherein the substituents are independently selected from (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, hydroxy, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy; phenyl-(C₃₋₅)cycloalkylene-(C₁₋₂)alkylene- whereinsaid (C₃₋₅)cycloalkylene optionally contains one ring oxygen atom, andwherein said phenyl is unsubstituted, or mono-substituted with halogen;phenyl-(C₁₋₂)alkylene-(C₃₋₅)cycloalkylene- wherein said(C₃₋₅)cycloalkylene optionally contains one ring oxygen atom; 5-memberedheteroaryl-(C₁₋₃)alkylene-, wherein said 5-membered heteroaryl containsone oxygen atom and one or two nitrogen atoms; and wherein said5-membered heteroaryl is unsubstituted, or mono-, or di-substituted;wherein the substituents are independently selected from (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;6-membered heteroaryl-(C₁₋₄)alkylene-, wherein said 6-memberedheteroaryl contains one or two nitrogen atoms; and wherein said6-membered heteroaryl is unsubstituted, or mono-, or di-substituted;wherein the substituents are independently selected from (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;wherein, in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl orpyrimidinyl may additionally be present in form of the respectiveN-oxide; 6-membered heteroaryl-(C₁₋₃)alkylene-, wherein said—(C₁₋₃)alkylene- is mono-substituted with hydroxy or trifluoromethyl;wherein said 6-membered heteroaryl contains one or two nitrogen atoms;or 6-membered heteroaryl-(C₃₋₅)cycloalkylene-, wherein said 6-memberedheteroaryl contains one or two nitrogen atoms; and wherein said6-membered heteroaryl is unsubstituted, or mono-, or di-substituted;wherein the substituents are independently selected from (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy;wherein, in case Ar³ represents pyridyl or pyrimidinyl, such pyridyl orpyrimidinyl may additionally be present in form of the respectiveN-oxide; 6-membered heteroaryl-(C₃₋₅)cycloalkylene-(C₁₋₂)alkylene-wherein said 6-membered heteroaryl contains one or two nitrogen atoms;and wherein said 6-membered heteroaryl is unsubstituted; and R^(N2)independently represents hydrogen, or (C₁₋₄)alkyl; or R^(N1) represents(C₁₋₃)alkyl; and R^(N2) represents hydrogen, or methyl; or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 5; wherein R¹ represents R^(N1)R^(N2)N—, wherein R^(N1) represents(C₃₋₆)cycloalkyl-(C₁₋₃)alkylene-, wherein said (C₃₋₆)cycloalkyloptionally contains one ring oxygen atom; phenyl-(C₁₋₄)alkylene- whereinsaid phenyl is unsubstituted, or mono-, or di-substituted; wherein thesubstituents are independently selected from (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; phenyl-(C₃₋₅)cycloalkylene-wherein said (C₃₋₅)cycloalkylene optionally contains one ring oxygenatom, and wherein said phenyl is unsubstituted, or mono-, ordi-substituted; wherein the substituents are independently selected from(C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, hydroxy, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy; 6-membered heteroaryl-(C₁₋₄)alkylene-, wherein said6-membered heteroaryl contains one or two nitrogen atoms; and whereinsaid 6-membered heteroaryl is unsubstituted, or mono-, ordi-substituted; wherein the substituents are independently selected from(C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy; wherein, in case Ar³ represents pyridyl orpyrimidinyl, such pyridyl or pyrimidinyl may additionally be present inform of the respective N-oxide; 6-memberedheteroaryl-(C₃₋₅)cycloalkylene-, wherein said 6-membered heteroarylcontains one or two nitrogen atoms; and wherein said 6-memberedheteroaryl is unsubstituted, or mono-, or di-substituted; wherein thesubstituents are independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein, in case Ar³represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl mayadditionally be present in form of the respective N-oxide; and R^(N2)independently represents hydrogen, or (C₁₋₄)alkyl; or a pharmaceuticallyacceptable salt thereof.
 9. The compound according to claim 5; whereinR¹ represents R^(N1)R^(N2)N—, wherein R^(N1) represents 6-memberedheteroaryl-(C₁₋₄)alkylene-, wherein said 6-membered heteroaryl containsone or two nitrogen atoms; and wherein said 6-membered heteroaryl isunsubstituted, or mono-, or di-substituted; wherein the substituents areindependently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,(C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein, in case Ar³represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl mayadditionally be present in form of the respective N-oxide; 6-memberedheteroaryl-(C₃₋₅)cycloalkylene-, wherein said 6-membered heteroarylcontains one or two nitrogen atoms; and wherein said 6-memberedheteroaryl is unsubstituted, or mono-, or di-substituted; wherein thesubstituents are independently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy,halogen, (C₁₋₃)fluoroalkyl, or (C₁₋₃)fluoroalkoxy; wherein, in case Ar³represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl mayadditionally be present in form of the respective N-oxide; and R^(N2)independently represents hydrogen or methyl. or a pharmaceuticallyacceptable salt thereof.
 10. The compound according to claim 7; whereinR² represents (C₃₋₈)cycloalkyl-(C₁₋₃)alkyl, wherein the (C₃₋₈)cycloalkylis unsubstituted; or mono-substituted wherein the substituent is(C₁₋₃)alkyl, fluoro, or (C₁₋₃)fluoroalkyl; or di-substituted withfluoro; or (C₃₋₈)cycloalkyl, wherein the (C₃₋₈)cycloalkyl isunsubstituted, or mono- or di-substituted wherein the substituents areindependently selected from (C₁₋₃)alkyl (especially methyl), or fluoro;or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 9; wherein R² represents unsubstituted(C₃₋₈)cycloalkyl-(C₁₋₃)alkyl; or unsubstituted (C₃₋₆)cycloalkyl; or(C₃₋₈)cycloalkyl, wherein the (C₃₋₈)cycloalkyl is di-substituted withfluoro; or (C₃₋₈)cycloalkyl-(C₁₋₃)alkyl; wherein the (C₃₋₈)cycloalkyl ismono-substituted with methyl, fluoro, or (C₁)fluoroalkyl; ordi-substituted with fluoro; or a pharmaceutically acceptable saltthereof.
 12. The compound according to claim 1 selected from:(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-methyl-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methylamide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methylamide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethylamide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethylamide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-oxo-pyrrolidin-1-yl)-ethyl]-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-oxo-pyrrolidin-1-yl)-ethyl]-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (thiazol-2-ylmethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (thiazol-2-ylmethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-o-tolyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-o-tolyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-methoxy-phenyl)-ethyl]-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-methoxy-phenyl)-ethyl]-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-chloro-phenyl)-ethyl]-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-chloro-phenyl)-ethyl]-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R,2S)-2-phenyl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S,2R)-2-phenyl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R,2S)-2-phenyl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S,2R)-2-phenyl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-p-tolyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-p-tolyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-m-tolyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-m-tolyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-2-hydroxy-2-phenyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-2-hydroxy-2-phenyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-(2-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-(2-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-2-ethoxy-1-methyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-2-ethoxy-1-methyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-2-ethoxy-1-methyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-2-ethoxy-1-methyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyrazin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyrazin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-cyclobutyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-cyclobutyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(5-fluoro-pyrimidin-2-yl)-ethyl]-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(5-fluoro-pyrimidin-2-yl)-ethyl]-amide;(3R,4R)-14(1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-14(1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-14(1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-14(1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-14(1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-14(1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-14(1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-14(1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-methoxy-1,1-dimethyl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyrazin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyrazin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyrazin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-cyclobutyl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-cyclobutyl-ethyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-14(1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-14(1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-14(1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-14(1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-14(1R,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-14(1R,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-14(1S,2R)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-14(1S,2S)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrazin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrazin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (cyano-dimethyl-methyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (cyano-dimethyl-methyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(4,6-dimethyl-pyrimidin-2-O-cyclopropyl]-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-((1R)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-((1S)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-((1R)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-((1S)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-ethyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-methyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1R)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1S)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1R)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-(1S)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-methyl-cyclopentyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-(2-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-(2-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-((1R)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-14(1S)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylicacid methyl-phenethyl-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid ((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid((1R)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid((1S)-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2-methoxy-ethyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1,1,2,2,2-d₅-ethyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid dimethylamide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (2-methoxy-1,1-dimethyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-phenyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((S)-2-hydroxy-1-phenyl-ethyl)-amide;(3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid benzylamide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(1R)-1-(2H-pyrazol-3-yl)-ethyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(1S)-1-(2H-pyrazol-3-yl)-ethyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-3-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-4-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-4-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-methyl-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-methyl-1-pyridin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1R)-1-isoxazol-3-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((1S)-1-isoxazol-3-yl-ethyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(1R)-1-(2H-pyrazol-3-yl)-ethyl]-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(1S)-1-(2H-pyrazol-3-yl)-ethyl]-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyridin-3-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclobutyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclobutyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(2-methoxy-phenyl)-cyclopropyl]-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1R,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2R)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-((1S,2S)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-cyano-cyclobutyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-cyano-cyclobutyl)-amide;(3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-(1-Difluoromethyl-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(4-fluoro-benzyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2,2-dimethyl-propyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isobutyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ethyl-methyl-amide;(3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-(2-pyridin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid methyl-(2-pyridin-2-yl-ethyl)-amide;(3S,4S)-14(1R)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-((1S)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3-fluoro-propyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyridin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Allyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Bicyclo[3.1.0]hex-3-yl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-propyl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-(3,3-Difluoro-cyclobutylmethyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-spiro[2.3]hex-5-yl-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-(Cyclopropyl-(d₂-methyl))-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-phenyl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-4-yl-cyclopropyl)-amide;1-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carbonyl)-amino]-cyclopropanecarboxylicacid ethyl ester;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-phenyl-cyclobutyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid benzyl-(2-fluoro-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(3-methoxy-phenyl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(2-trifluoromethyl-phenyl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(2-fluoro-phenyl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [2-(2-chloro-phenyl)-ethyl]-amide;5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(3-chloro-phenyl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(4-methyl-thiazol-2-yl)-cyclobutyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(2-methoxy-phenyl)-ethyl]-amide;(3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(S)-1-(2-methoxy-phenyl)-ethyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(2-methoxy-phenyl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(3-bromo-phenyl)-ethyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(2-hydroxy-phenyl)-cyclopropyl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(1-oxy-pyrimidin-2-yl)-cyclopropyl]-amide;5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide;5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid[(3S,4S)-1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4-yl]-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyrimidin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((S)-1-pyrimidin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [1-(3-fluoro-phenyl-2-yl)-cyclopropyl]-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((R)-1-pyrimidin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid ((S)-1-pyrimidin-2-yl-ethyl)-amide;(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (3-benzyl-oxetan-3-yl)-amide;(3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (3-phenyl-oxetan-3-ylmethyl)-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylicacid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide;(3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylicacid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [3-(3-chloro-phenyl)-oxetan-3-yl]-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;(3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid [(S)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide;(3R,4R)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1);(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dimethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide;(3S,4S)-1-Cyclopropylmethyl-4-{[4-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylicacid (1-pyrimidin-2-yl-cyclopropyl)-amide; or a pharmaceuticallyacceptable salt thereof.
 13. A pharmaceutical composition comprising, asactive principle, one or more compounds according to claim 1, or apharmaceutically acceptable salt thereof, and at least onetherapeutically inert excipient.
 14. (canceled)
 15. (canceled) 16.(canceled)
 17. A method for the prophylaxis or treatment of cancer,autoimmune disorders, inflammatory diseases, transplant rejection, orfibrosis; comprising administering to a subject in need thereof aneffective amount of a compound of formula (I) as defined in claim 1, ora pharmaceutically acceptable salt thereof.
 18. A method of treatingtumors comprising administering an effective amount of the compound offormula (Ia) according to claim 1, or a pharmaceutically acceptable saltthereof, wherein said effective amount leads to a change of tumorproperties, and wherein said modification is achieved by modulating theCXCL11/CXCL12 receptor pathway.
 19. A method of modulating an immuneresponse comprising the administration of an effective amount of thecompound of formula (Ia) according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein said effective amount modulates aninflammatory disease and wherein said response is mediated by theCXCL11/CXCL12 receptor pathway.
 20. A compound of formula (Ib)

wherein the two substituents of the piperidine ring: R¹—CO— and—NH—CO—Ar¹—Ar², are in relative trans-configuration; Ar¹ represents anunsubstituted 5-membered heteroarylene group containing one sulfur ringatom and one or two nitrogen ring atoms, wherein the —NH—CO— group andAr² are attached in meta arrangement to ring atoms of Ar¹; Ar²represents phenyl, or 6-membered heteroaryl; wherein said phenyl or6-membered heteroaryl independently is mono-, di- or tri-substituted,wherein the substituents are independently selected from fluoro, chloro,methyl, cyano, methoxy, or (C₁)fluoroalkyl; R¹ representsR^(N1)R^(N2)N—, wherein R^(N1) represents hydrogen; (C₁₋₆)alkyl;(C₁₋₆)alkyl which is mono-substituted with hydroxy; (C₁₋₃)alkoxy;2-hydroxy-ethoxy; —CO—NH₂; SO₂—(C₁₋₃)alkyl; cyano; (C₁₋₃)fluoroalkoxy;NR^(N3)R^(N4), wherein R^(N3) and R^(N4) independently representhydrogen or (C₁₋₄)alkyl; (C₂₋₆)alkynyl; (C₂₋₅)fluoroalkyl; (C₁₋₄)alkoxy;2-(2-oxo-pyrrolidin-1-yl)-ethyl; a group -L¹-Cy¹; wherein L¹ representsa direct bond, —(C₁₋₃)alkylene-, or —(C₃₋₅)cycloalkylene-; and Cy¹represents (C₃₋₆)cycloalkyl, wherein said (C₃₋₆)cycloalkyl optionallycontains one ring oxygen atom; wherein said (C₃₋₆)cycloalkylindependently is unsubstituted; or mono-substituted with fluoro, methyl,or hydroxy, —CO—(C₁₋₄)alkoxy, or cyano; or di-substituted with fluoro,or tri-substituted with methyl and two fluoro; a group -L²-Ar³, whereinL² represents a direct bond, —(C₁₋₄)alkylene-;*—(C₃₋₅)cycloalkylene-(C₀₋₂)alkylene- wherein said (C₃₋₅)cycloalkyleneoptionally contains one ring oxygen atom, wherein the asterisk indicatesthe bond to which Ar³ is attached; *—(C₁₋₂)alkylene-(C₃₋₅)cycloalkylene-wherein said (C₃₋₅)cycloalkylene optionally contains one ring oxygenatom, wherein the asterisk indicates the bond to which Ar³ is attached;or —(C₁₋₃)alkylene- which is mono-substituted with hydroxy,trifluoromethyl, or —CO—(C₁₋₄)alkoxy; and Ar³ represents phenyl, or 5-or 6-membered heteroaryl; wherein said phenyl or 5- or 6-memberedheteroaryl independently is unsubstituted, or mono-, or di-substituted;wherein the substituents are independently selected from (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, hydroxy, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy; wherein, in case Ar³ represents 6-memberedheteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinylmay additionally be present in form of the respective N-oxide; andR^(N2) independently represents hydrogen, (C₁₋₄)alkyl, or(C₂₋₃)fluoroalkyl; or R^(N1) and R^(N2) together with the nitrogen atomto which they are attached to form a 4- to 6-membered ring selected fromazetidinyl, pyrrolidinyl or piperidinyl; each independentlyunsubstituted; or mono-substituted with fluoro, methyl, or hydroxy; ordi-substituted with fluoro; or mono-substituted with Ar⁴, wherein Ar⁴represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenylor 5- or 6-membered heteroaryl independently is unsubstituted, or mono-,or di-substituted; wherein the substituents are independently selectedfrom (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy; or morpholinyl; R² represents hydrogen; (C₁₋₆)alkyl;(C₂₋₆)alkyl which is mono-substituted with (C₁₋₃)alkoxy, or hydroxy;(C₃₋₅)alkenyl (especially allyl); cyano-methyl; (C₂₋₃)fluoroalkyl;(C₃₋₈)cycloalkyl-(C₀₋₃)alkyl; wherein the (C₃₋₈)cycloalkyl isunsubstituted, or mono- or di-substituted wherein the substituents areindependently selected from (C₁₋₃)alkyl, fluoro, hydroxy,hydroxy-(C₁₋₃)alkyl, (C₁₋₃)alkoxy, or (C₁₋₃)fluoroalkyl; thietan-3-yl;(C₃₋₈)cycloalkenyl-(C₁₋₃)alkyl; or Ar⁵—CH₂— wherein Ar⁵ representsphenyl, or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or6-membered heteroaryl independently is unsubstituted, or mono- ordi-substituted wherein the substituents are independently selected from(C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, (C₁₋₃)fluoroalkyl, or(C₁₋₃)fluoroalkoxy; and R³ represents hydrogen, or methyl; or apharmaceutically acceptable salt thereof.
 21. The compound of formula(Ib) as defined in claim 20 which are also compounds of Formula (Ibs),wherein the two substituents of the piperidine ring: R¹—CO— and—NH—CO—Ar¹—Ar², are in relative trans-configuration, wherein theabsolute configuration of the two chiral carbon atoms in position 3 and4 of the piperidine ring is (3S,4S):

or a pharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition comprising, as active principle, one or more compoundsaccording to claim 20, or a pharmaceutically acceptable salt thereof,and at least one therapeutically inert excipient.
 23. A method for theprophylaxis or treatment of cancer, autoimmune disorders, inflammatorydiseases, transplant rejection, or fibrosis; comprising administering toa subject in need thereof an effective amount of a compound of formula(Ia) as defined in claim 20, or a pharmaceutically acceptable saltthereof.